Parkinson's Disease

Complex MONDO:0005180 Pathograph 17 Neurodegenerative Disease Movement Disorder
0
Mappings
0
Definitions
0
Inheritance
12
Pathophysiology
0
Histopathology
7
Phenotypes
17
Pathograph
5
Genes
6
Treatments
0
Subtypes
0
Differentials
7
Datasets
0
Trials
4
Models
📚

References

4
DOI:10.2147/ndt.s540718
Updates on Parkinson’s Disease
No top-level findings curated for this source.
DOI:10.3389/fnagi.2025.1617106
Understanding Parkinson’s disease: current trends and its multifaceted complications
No top-level findings curated for this source.
DOI:10.3390/cells14151161
Parkinson’s Disease: Bridging Gaps, Building Biomarkers, and Reimagining Clinical Translation
No top-level findings curated for this source.
DOI:10.3390/ijms25137183
A Comprehensive Approach to Parkinson’s Disease: Addressing Its Molecular, Clinical, and Therapeutic Aspects
No top-level findings curated for this source.
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Pathophysiology

12
Dopaminergic Neuron Loss
Progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta leads to dopamine deficiency in the striatum, causing motor symptoms. Symptoms appear after 60-80% neuron loss.
Dopaminergic Neuron link
Dopamine Biosynthesis link
Show evidence (1 reference)
PMID:37048085 SUPPORT
"Tremor, shaking, movement problems, and difficulty with balance and coordination are among the hallmarks, and dopaminergic neuronal loss in substantia nigra pars compacta of the brain and aggregation of intracellular protein α-synuclein are the pathological characterizations."
This review confirms that dopaminergic neuronal loss in the substantia nigra pars compacta is a pathological hallmark of Parkinson's disease, supporting the core mechanism of dopaminergic neuron degeneration.
Alpha-Synuclein Aggregation
Misfolded alpha-synuclein protein accumulates to form Lewy bodies and Lewy neurites. These aggregates spread through the nervous system in a prion-like manner, contributing to neurodegeneration.
inclusion body assembly link
Show evidence (3 references)
PMID:38245249 SUPPORT
"Parkinson's disease is a progressive neurodegenerative condition associated with the deposition of aggregated α-synuclein."
This authoritative Lancet review establishes that aggregated α-synuclein deposition is a defining feature of Parkinson's disease pathogenesis.
PMID:38245249 SUPPORT
"Biochemical studies, investigation of transplanted neurons in patients with Parkinson's disease, and cell and animal model studies suggest that abnormal aggregation of α-synuclein and spreading of pathology between the gut, brainstem, and higher brain regions probably underlie the development..."
This provides direct evidence for the prion-like spreading mechanism of α-synuclein pathology across neural networks, supporting the mechanism of trans-neuronal propagation.
PMID:36598534 SUPPORT
"Parkinson's disease (PD) is the second most common neurodegenerative disease, and is characterized by accumulation of α-synuclein (α-syn)."
Confirms that α-synuclein accumulation is a key pathological characterization of PD, reinforcing the central role of protein aggregation in disease pathology.
Mitochondrial Dysfunction
Impaired mitochondrial function, particularly complex I deficiency, leads to oxidative stress and neuronal death. Multiple PD genes (PINK1, Parkin, DJ-1) regulate mitochondrial quality control.
mitochondrion organization link
Show evidence (3 references)
PMID:38245249 SUPPORT
"At a cellular level, abnormal mitochondrial, lysosomal, and endosomal function can be identified in both monogenic and sporadic Parkinson's disease, suggesting multiple potential treatment approaches."
This establishes that mitochondrial dysfunction is a common cellular feature across both genetic and sporadic forms of PD, supporting its central role in disease pathogenesis.
PMID:25611507 SUPPORT
"Biochemical and genetic studies reveal that the products of two genes that are mutated in autosomal recessive parkinsonism, PINK1 and Parkin, normally work together in the same pathway to govern mitochondrial quality control, bolstering previous evidence that mitochondrial damage is involved in..."
This directly supports the role of PINK1 and Parkin genes in mitochondrial quality control and confirms that mitochondrial damage is involved in PD pathogenesis.
PMID:27911343 SUPPORT
"For the past 30 years, mitochondrial dysfunction has been hypothesized to play a central role in the pathobiology of this devastating neurodegenerative disease. The identifications of mutations in genes encoding PINK1 (PTEN-induced kinase 1) and Parkin (E3 ubiquitin ligase) in familial PD and..."
This review confirms the long-standing central role of mitochondrial dysfunction in PD and validates the connection between PINK1/Parkin mutations and mitochondrial quality control defects.
Neuroinflammation
Activated microglia and astrocytes contribute to neurodegeneration through release of pro-inflammatory cytokines and oxidative stress.
Microglia link Astrocyte link
Show evidence (3 references)
PMID:38245249 SUPPORT
"Recent work has also highlighted maladaptive immune and inflammatory responses, possibly triggered in the gut, that accelerate the pathogenesis of Parkinson's disease."
This establishes that maladaptive immune and inflammatory responses play an active role in accelerating PD pathogenesis, supporting the neuroinflammation mechanism.
PMID:37048085 SUPPORT
"Neuroinflammation has emerged as an involving mechanism at the initiation and development of PD. It is a complex network of interactions comprising immune and non-immune cells in addition to mediators of the immune response. Microglia, the resident macrophages in the CNS, take on the leading..."
This directly supports the role of microglia-mediated neuroinflammation in PD initiation and progression, confirming the importance of microglial activation in disease pathology.
PMID:36598534 SUPPORT
"Neuroinflammation driven by microglia is an important pathological manifestation of PD. α-Syn is a crucial marker of PD, and its accumulation leads to microglia M1-like phenotype polarization, activation of NLRP3 inflammasomes, and impaired autophagy and phagocytosis in microglia."
This links α-synuclein accumulation to microglial activation and pro-inflammatory M1 phenotype polarization, supporting the mechanism by which neuroinflammation contributes to neurodegeneration in PD.
Autophagy-Lysosome Pathway Dysfunction
Impairment of the autophagy-lysosome pathway disrupts clearance of misfolded proteins including alpha-synuclein. Multiple PD genes (GBA, LRRK2, VPS35, ATP13A2) regulate lysosomal function, and their mutations impair protein degradation capacity leading to toxic protein accumulation.
Dopaminergic Neuron link
Autophagy link Chaperone-mediated Autophagy link
Show evidence (1 reference)
PMID:31761667 SUPPORT
"In recent years, multiple lines of evidence from human genetic and molecular studies have highlighted the importance of the autophagy lysosomal pathway (ALP) in Parkinson's disease (PD). Genes such as GBA and LRRK2, which harbor some of the most common mutations associated with PD, have..."
This review establishes the genetic basis for autophagy-lysosome dysfunction in PD, identifying key genes and their mechanistic roles.
Gut-Brain Axis Dysfunction
Alterations in gut microbiota composition trigger intestinal inflammation and may initiate alpha-synuclein misfolding in enteric neurons. Pathological alpha-synuclein spreads from gut to brain via the vagus nerve, supporting the gut-first hypothesis of PD pathogenesis.
Enteric Neuron link Enteroendocrine Cell link
Inflammatory Response link
Show evidence (2 references)
PMID:38098067 SUPPORT
"Various microorganisms inhabiting the gastrointestinal tract can profoundly influence the physiopathology of the central nervous system through neurological, endocrine, and immune system pathways involved in the microbiota-gut-brain axis."
This review establishes the gut microbiota-brain connection in PD pathophysiology.
PMID:37449597 SUPPORT
"The vagus nerve, the main component of the parasympathetic nervous system, is involved in the regulation of immune response, digestion, heart rate, and control of mood."
Establishes the vagus nerve as the key anatomical connection mediating gut-brain communication in PD.
Oxidative Stress
Excessive reactive oxygen species from dopamine metabolism and mitochondrial dysfunction causes lipid peroxidation, protein carbonylation, and DNA damage. Dopamine auto-oxidation generates toxic quinones that preferentially damage substantia nigra neurons.
Dopaminergic Neuron link
Response to Oxidative Stress link ROS Metabolic Process link
Show evidence (1 reference)
PMID:37303175 SUPPORT
"Reactive oxygen species (ROS)-induced oxidative stress triggers the vicious cycle leading to the degeneration of dopaminergic neurons in the nigra pars compacta."
This review directly describes the mechanism by which oxidative stress drives dopaminergic neurodegeneration.
Calcium Dysregulation
Substantia nigra dopaminergic neurons rely on L-type calcium channels (CaV1.3) for autonomous pacemaking, making them uniquely vulnerable to calcium-mediated toxicity. Disrupted calcium homeostasis in mitochondria, ER, and lysosomes contributes to oxidative stress and cell death.
Dopaminergic Neuron link
Calcium Ion Homeostasis link Calcium Ion Transport link
Show evidence (1 reference)
PMID:35339179 SUPPORT
"Calcium (Ca2+) plays a central role in regulating many cellular processes and influences cell survival."
This review establishes the fundamental role of calcium channel dysregulation in PD pathogenesis.
Endoplasmic Reticulum Stress
Accumulation of misfolded proteins in the ER activates the unfolded protein response (UPR). Chronic ER stress overwhelms protective mechanisms, triggering apoptotic pathways. Alpha-synuclein aggregates and GBA mutations directly impair ER function.
Dopaminergic Neuron link
ER Stress Response link Unfolded Protein Response link
Show evidence (1 reference)
PMID:38026955 SUPPORT
"Accumulating evidence shows that endoplasmic reticulum (ER) stress occurring in the SNpc DA neurons is an early event in the development of PD."
This review establishes ER stress as an early and central event in PD pathogenesis.
Synaptic Dysfunction
Impaired synaptic vesicle recycling, particularly defects in clathrin-mediated endocytosis, represents an early feature of PD. Multiple PD genes (DNAJC6, SYNJ1, LRRK2) regulate synaptic vesicle trafficking, and their dysfunction leads to synaptic failure before overt neurodegeneration.
Dopaminergic Neuron link
Synaptic Vesicle Cycle link Synaptic Vesicle Endocytosis link
Show evidence (1 reference)
PMID:38595283 SUPPORT
"Notably, several of these genes are linked to the synaptic vesicle recycling process, particularly the clathrin-mediated endocytosis pathway. This suggests that impaired synaptic vesicle recycling might represent an early feature of Parkinson's disease"
Establishes synaptic vesicle endocytosis dysfunction as an early feature of PD.
Iron Accumulation and Ferroptosis
Abnormal iron deposition in the substantia nigra promotes ferroptosis, an iron-dependent form of cell death characterized by lipid peroxidation. Iron catalyzes Fenton reactions generating hydroxyl radicals, and dysregulated iron metabolism contributes to oxidative damage.
Dopaminergic Neuron link
Iron Ion Homeostasis link Ferroptosis link
Show evidence (1 reference)
PMID:39218077 SUPPORT
"Parkinson's disease (PD) is a prevalent and advancing age-related neurodegenerative disorder, distinguished by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Iron regional deposit in SNpc is a significant pathological characteristic of PD."
This review establishes iron accumulation as a significant pathological characteristic and mechanistic driver of PD.
Blood-Brain Barrier Dysfunction
Altered tight junction proteins, transporter dysfunction, and alpha-synuclein accumulation compromise BBB integrity. BBB breakdown allows infiltration of peripheral immune cells and blood-borne molecules, amplifying neuroinflammation.
Brain Endothelial Cell link Pericyte link Astrocyte link
BBB Maintenance link Vascular Permeability link
Show evidence (1 reference)
PMID:39075566 SUPPORT
"There is increasing evidence for blood-brain barrier (BBB) alterations in Parkinson's disease (PD), the second most common neurodegenerative disorder with rapidly rising prevalence."
This comprehensive 2024 review establishes BBB dysfunction as an emerging mechanism in PD pathogenesis.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Parkinson's Disease Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

7
Digestive 1
Constipation FREQUENT Constipation (HP:0002019)
Common non-motor symptom
Show evidence (1 reference)
PMID:7845407 SUPPORT
"We investigated the role of anorectal manometry in evaluating constipation and anorectal function in 15 patients with Parkinson's disease (PD) and compared results with those of 9 patients with idiopathic constipation (IC) and 8 control (C) subjects."
This study directly evaluates constipation in PD patients, supporting constipation as a common non-motor symptom.
Head and Neck 1
Hyposmia FREQUENT Hyposmia (HP:0004409)
Often precedes motor symptoms by years
Show evidence (1 reference)
PMID:24136244 SUPPORT
"Hyposmia, identified as reduced sensitivity to odor, is a common non-motor symptom of Parkinson's disease (PD) that antedates the typical motor symptoms by several years. It occurs in ∼90% of early-stage cases of PD."
This establishes hyposmia as a highly prevalent prodromal symptom that precedes motor symptoms, supporting its importance as an early marker of PD.
Musculoskeletal 1
Rigidity VERY_FREQUENT Rigidity (HP:0002063)
Cogwheel or lead-pipe rigidity
Show evidence (1 reference)
PMID:17955331 SUPPORT
"Participants are screened in the baseline and follow-up examinations for cardinal signs of parkinsonism (resting tremor, rigidity, bradykinesia or impaired postural reflexes)."
This confirms rigidity as a cardinal sign of parkinsonism relevant to PD.
Nervous System 4
Resting Tremor VERY_FREQUENT Resting tremor (HP:0002322)
Classic "pill-rolling" tremor at rest
Show evidence (1 reference)
PMID:17955331 SUPPORT
"Participants are screened in the baseline and follow-up examinations for cardinal signs of parkinsonism (resting tremor, rigidity, bradykinesia or impaired postural reflexes)."
This identifies resting tremor as a cardinal sign used to detect parkinsonism, supporting it as a core PD phenotype.
Bradykinesia VERY_FREQUENT Bradykinesia (HP:0002067)
Slowness of movement, required for diagnosis
Show evidence (1 reference)
PMID:17955331 SUPPORT
"Participants are screened in the baseline and follow-up examinations for cardinal signs of parkinsonism (resting tremor, rigidity, bradykinesia or impaired postural reflexes)."
This lists bradykinesia among the cardinal signs of parkinsonism, supporting its central role in PD.
Postural Instability FREQUENT Postural instability (HP:0002172)
Develops in later disease stages
Show evidence (1 reference)
PMID:17955331 SUPPORT
"Participants are screened in the baseline and follow-up examinations for cardinal signs of parkinsonism (resting tremor, rigidity, bradykinesia or impaired postural reflexes)."
This supports postural instability as a cardinal parkinsonian sign captured in PD assessments.
Depression FREQUENT Depression (HP:0000716)
Show evidence (1 reference)
PMID:41301797 SUPPORT
"Depressive symptoms were similar across groups, but in prodromal PD, higher GDS scores were associated with worse UPDRS III scores (p = 0.02), as well as higher freezing and fall scores."
This indicates depressive symptoms are present and clinically relevant in PD, supporting depression as a non-motor phenotype.
🧬

Genetic Associations

5
SNCA (Causative)
Show evidence (1 reference)
PMID:9197268 SUPPORT
"A mutation was identified in the alpha-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype."
This landmark 1997 Science paper identified the first SNCA mutations in familial PD with autosomal dominant inheritance, establishing SNCA as a causative gene for Parkinson's disease.
LRRK2 (Risk Factor)
Show evidence (1 reference)
PMID:19945904 SUPPORT
"The LRRK2 G2019S mutation is the most frequent known cause of familial and sporadic Parkinson's disease."
This systematic review establishes that LRRK2 G2019S is the most common genetic cause of both familial and sporadic PD, supporting its role as the major genetic risk factor.
GBA (Risk Factor)
Show evidence (1 reference)
PMID:30097731 SUPPORT
"DLB shares risk loci with AD, in the APOE E4 allele, and with PD, in variation at GBA and SNCA."
This identifies GBA as a genetic risk locus shared with PD, supporting its role as a PD risk factor.
PARK2 (Causative)
Show evidence (1 reference)
PMID:25611507 SUPPORT
"Biochemical and genetic studies reveal that the products of two genes that are mutated in autosomal recessive parkinsonism, PINK1 and Parkin, normally work together in the same pathway to govern mitochondrial quality control, bolstering previous evidence that mitochondrial damage is involved in..."
This establishes Parkin (PARK2) as a gene mutated in autosomal recessive parkinsonism, supporting its causative role.
PINK1 (Causative)
Show evidence (1 reference)
PMID:25611507 SUPPORT
"Biochemical and genetic studies reveal that the products of two genes that are mutated in autosomal recessive parkinsonism, PINK1 and Parkin, normally work together in the same pathway to govern mitochondrial quality control, bolstering previous evidence that mitochondrial damage is involved in..."
This identifies PINK1 mutations in autosomal recessive parkinsonism, supporting its causative role in PD.
💊

Treatments

6
Levodopa/Carbidopa
Action: pharmacotherapy MAXO:0000058
Agent: levodopa ↗ carbidopa ↗
Gold standard treatment, replaces dopamine precursor.
Show evidence (1 reference)
PMID:27577098 SUPPORT
"The symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been constantly optimized using pharmacotherapy (L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine), deep brain stimulation, and physiotherapy."
This review identifies L-Dopa as a core pharmacotherapy for PD motor symptoms.
Dopamine Agonists
Action: pharmacotherapy MAXO:0000058
Directly stimulate dopamine receptors.
Show evidence (1 reference)
PMID:27577098 SUPPORT
"The symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been constantly optimized using pharmacotherapy (L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine), deep brain stimulation, and physiotherapy."
This review identifies dopamine agonists as part of standard pharmacotherapy for PD.
MAO-B Inhibitors
Action: pharmacotherapy MAXO:0000058
Prevent dopamine breakdown (selegiline, rasagiline).
Show evidence (1 reference)
PMID:27577098 SUPPORT
"The symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been constantly optimized using pharmacotherapy (L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine), deep brain stimulation, and physiotherapy."
This review lists MAO-B inhibitors among standard PD pharmacotherapies.
COMT Inhibitors
Action: pharmacotherapy MAXO:0000058
Extend levodopa duration (entacapone).
Show evidence (1 reference)
PMID:27577098 SUPPORT
"The symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been constantly optimized using pharmacotherapy (L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine), deep brain stimulation, and physiotherapy."
This review lists COMT inhibitors among standard PD pharmacotherapies.
Deep Brain Stimulation
Action: surgical procedure MAXO:0000004
Surgical therapy for advanced motor fluctuations.
Show evidence (1 reference)
PMID:27577098 SUPPORT
"The symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been constantly optimized using pharmacotherapy (L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine), deep brain stimulation, and physiotherapy."
This review identifies deep brain stimulation as a standard symptomatic therapy for PD.
Physical Therapy
Action: physical therapy MAXO:0000011
Maintains mobility and reduces fall risk.
Show evidence (1 reference)
PMID:27577098 SUPPORT
"The symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been constantly optimized using pharmacotherapy (L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine), deep brain stimulation, and physiotherapy."
This review lists physiotherapy as part of symptomatic treatment for PD.
🌍

Environmental Factors

3
Pesticide Exposure
Rotenone and paraquat linked to increased risk
Show evidence (1 reference)
PMID:15177059 SUPPORT
"there is general agreement that smoking and exposure to pesticides affect the probability of developing PD."
This review supports pesticide exposure as an environmental factor influencing PD risk.
Rural Living
Associated with pesticide/herbicide exposure
Show evidence (1 reference)
PMID:15177059 PARTIAL
"While clear links to rural living, dietary factors, exposure to metals, head injury, and exposure to infectious diseases during childhood have not been established, there is general agreement that smoking and exposure to pesticides affect the probability of developing PD."
This review notes that clear links to rural living are not established, indicating mixed evidence for this risk factor.
Head Trauma
Possible risk factor
Show evidence (1 reference)
PMID:36781627 SUPPORT
"The risk ratio of TBI among PD and controls by a combination of 15 studies using a random-effect model was 1.48 (95% CI 1.22-1.74)."
This meta-analysis supports head trauma (TBI) as a risk factor for developing PD.
📊

Related Datasets

7
Large-scale metagenomics of Parkinson's disease gut microbiome sra:PRJNA834801
Shotgun metagenomics from the NeuroGenetics Research Consortium (NGRC) with over 30% of species, genes and pathways showing altered abundances in PD. Identified polymicrobial clusters and competitive relationships.
human gut metagenome WGS
fecal sample
Conditions: Parkinson's disease healthy controls
PMID:36357667
Nature Communications 2022 - largest PD metagenomics to date
Show evidence (1 reference)
PMID:37449597 SUPPORT
"This critical review of the literature shows that there is a close link between the microbiome, the gut, and the brain in Parkinson's disease."
This supports the relevance of gut microbiome datasets to PD mechanisms.
Multi-omics analysis of PD gut microbiome gene expression sra:PRJNA782492
Integrated metagenomics and metatranscriptomics analyzing microbiome gene co-expression networks in Parkinson's disease. Observed significant depletion of hub genes in PD patients.
human gut metagenome WGS
fecal sample
Conditions: Parkinson's disease healthy controls
npj Biofilms and Microbiomes 2025 - multi-omics approach
Show evidence (1 reference)
PMID:37449597 SUPPORT
"This critical review of the literature shows that there is a close link between the microbiome, the gut, and the brain in Parkinson's disease."
This supports the relevance of gut microbiome datasets to PD mechanisms.
Longitudinal gut microbiome in Parkinson's disease sra:PRJNA808166
Longitudinal study investigating gut microbiome changes in PD patients and impact of device-assisted therapies. Tracks microbiome alterations with disease progression.
human gut metagenome
fecal sample
Conditions: Parkinson's disease baseline Parkinson's disease follow-up
Frontiers Aging Neuroscience 2022 - longitudinal design
Show evidence (1 reference)
PMID:37449597 SUPPORT
"This critical review of the literature shows that there is a close link between the microbiome, the gut, and the brain in Parkinson's disease."
This supports the relevance of gut microbiome datasets to PD mechanisms.
PD gut microbiome meta-analysis cohort sra:PRJNA530401
Metagenomic sequencing data from PD patients and controls contributing to cross-cohort meta-analyses. Identified alterations linked to intestinal inflammation including reduced butyrate producers.
human gut metagenome WGS
fecal sample
Conditions: Parkinson's disease healthy controls
npj Parkinson's Disease 2021 - meta-analysis contributing cohort
Show evidence (1 reference)
PMID:37449597 SUPPORT
"This critical review of the literature shows that there is a close link between the microbiome, the gut, and the brain in Parkinson's disease."
This supports the relevance of gut microbiome datasets to PD mechanisms.
Metabolomics of sebum reveals lipid dysregulation in Parkinson's disease metabolights:MTBLS2266
LC-MS sebum metabolomics in Parkinson's disease, including drug-naive and medicated cohorts, compared with well-matched controls to identify lipid pathway alterations.
human METABOLOMICS n=274
Conditions: Parkinson's disease drug-naive Parkinson's disease medicated Parkinson's disease healthy controls
Findings
Sebum metabolomics in PD shows alterations in lipid metabolism pathways, including the carnitine shuttle, sphingolipid metabolism, arachidonic acid metabolism and fatty acid biosynthesis.
Show evidence (1 reference)
metabolights:MTBLS2266 SUPPORT
"Pathway enrichment analysis shows alterations in lipid metabolism related to the carnitine shuttle, sphingolipid metabolism, arachidonic acid metabolism and fatty acid biosynthesis."
The dataset description reports lipid pathway alterations detected in sebum metabolomics for PD.
LC-MS profiling of 274 participants detected metabolites predictive of PD phenotype.
Show evidence (1 reference)
metabolights:MTBLS2266 SUPPORT
"We used liquid chromatography-mass spectrometry (LC-MS) to analyse 274 samples from participants (80 drug naïve PD, 138 medicated PD and 56 well matched control subjects) and detected metabolites that could predict PD phenotype."
The dataset description specifies LC-MS profiling and the PD/control cohort sizes.
PMID:33707447
Metabolomics profiling of sebum as a non-invasive biofluid for PD.
Show evidence (1 reference)
metabolights:MTBLS2266 SUPPORT
"Here, we use a metabolomics profiling approach to identify changes to lipids in PD observed in sebum, a non-invasively available biofluid."
Establishes that the dataset focuses on PD sebum metabolomics.
Metabolomic Changes in Idiopathic and GBA1 Parkinson’s Disease metabolights:MTBLS10743
Mass spectrometry metabolomics comparing idiopathic Parkinson's disease and GBA1-associated Parkinson's disease cohorts with controls.
human METABOLOMICS
Conditions: idiopathic Parkinson's disease GBA1-associated Parkinson's disease healthy controls
Findings
Metabolomic signatures differ between GBA1-PD and idiopathic PD in sebum and serum with good specificity and sensitivity.
Show evidence (1 reference)
metabolights:MTBLS10743 SUPPORT
"Differences in metabolomic signatures were seen between ... GBA1-PD and iPD in sebum and serum with good specificity and sensitivity."
The dataset description reports discriminative metabolomic signatures between GBA1-PD and idiopathic PD.
Serum pathways implicated include sphingolipid metabolism, amino sugar metabolism and amino acid pathways, while sebum features are hypothesised to be lipid degradation products.
Show evidence (1 reference)
metabolights:MTBLS10743 SUPPORT
"Significant pathways in serum included sphingolipid metabolism, amino sugar metabolism and amino acid pathways, whereas significant features between groups in sebum are hypothesised to be lipid degradation products."
The dataset description lists pathway-level differences in serum and hypothesized lipid degradation products in sebum.
Preprint dataset describing metabolic changes in idiopathic vs GBA1 PD.
Show evidence (1 reference)
metabolights:MTBLS10743 SUPPORT
"Here, we use mass spectrometry based metabolomics to analyse serum and sebum samples from 50 genotyped participants and find differences in lipid and sugar regulation, oxidative stress and the production of amino acids and neurotransmitters which distinguish ... GBA1-PD from iPD."
Establishes the dataset's serum and sebum metabolomics design distinguishing GBA1-PD from idiopathic PD.
A multi-region single nucleus transcriptomic atlas of Parkinson's disease cellxgene:d5d0df8f-4eee-49d8-a221-a288f50a1590
Single-nucleus RNA-seq atlas of Parkinson's disease spanning multiple brain regions, providing cell-type-resolved transcriptomic profiles of dopaminergic neurons and glial populations in PD and healthy controls.
human SINGLE CELL RNA SEQ
brain tissue
Conditions: Parkinson's disease healthy controls
PMID:39317733
CZI CELLxGENE collection. DOI 10.1038/s41597-024-04117-y. Multi-region snRNA-seq atlas enabling virtual cell model training on PD-relevant cell states.
🧮

Computational Models

4
Alpha-Synuclein Aggregation BST Model KINETIC
Biochemical Systems Theory (BST) model of alpha-synuclein aggregation kinetics in dopaminergic neurons. Integrates dopamine metabolism, ubiquitin-proteasome system, and lysosomal degradation pathways. Simulates effects of oxidative stress and proteasome inhibition on synuclein accumulation.
Repository ↗ PMID:19136028 ↗
First comprehensive kinetic model of PD-related protein aggregation
Whole Dopaminergic Neuron SBML Model SBML KINETIC
Large-scale Systems Biology Markup Language (SBML) model of dopaminergic neuron containing 139 reactions and 111 metabolites. Captures dopamine synthesis, vesicular storage, release, reuptake, and degradation alongside mitochondrial function and oxidative stress.
Repository ↗ PMID:24196439 ↗
Enables simulation of drug effects on dopaminergic neurotransmission
Basal Ganglia Spiking Neural Network PHYSIOLOGICAL
Computational model of the basal ganglia circuit capturing dopamine-modulated dynamics between striatum, globus pallidus, subthalamic nucleus, and substantia nigra. Simulates pathological beta-band oscillations and motor dysfunction in PD.
PMID:29666208 ↗
Models circuit-level effects of dopamine depletion and DBS therapy
Alpha-Synuclein Prion-like Spreading Model AGENT_BASED
Network diffusion model simulating prion-like propagation of misfolded alpha-synuclein through brain connectome. Uses graph-theoretical approach to predict spatial patterns of neurodegeneration from initial seeding sites.
Predicts Braak staging patterns from connectivity-based spreading
{ }

Source YAML

click to show 
name: Parkinson's Disease
creation_date: '2025-12-18T17:01:35Z'
updated_date: '2026-03-21T23:02:20Z'
category: Complex
parents:
- Neurodegenerative Disease
- Movement Disorder
disease_term:
  preferred_term: Parkinson disease
  term:
    id: MONDO:0005180
    label: Parkinson disease
pathophysiology:
- name: Dopaminergic Neuron Loss
  description: >
    Progressive degeneration of dopaminergic neurons in the substantia nigra
    pars compacta leads to dopamine deficiency in the striatum, causing motor
    symptoms. Symptoms appear after 60-80% neuron loss.
  cell_types:
  - preferred_term: Dopaminergic Neuron
    term:
      id: CL:0000700
      label: dopaminergic neuron
  biological_processes:
  - preferred_term: Dopamine Biosynthesis
    term:
      id: GO:0042416
      label: dopamine biosynthetic process
  downstream:
  - target: Resting Tremor
    evidence:
    - reference: PMID:37048085
      reference_title: "Microglia Mediated Neuroinflammation in Parkinson's Disease."
      supports: SUPPORT
      snippet: "Tremor, shaking, movement problems, and difficulty with balance and
        coordination are among the hallmarks, and dopaminergic neuronal loss in substantia
        nigra pars compacta of the brain and aggregation of intracellular protein
        α-synuclein are the pathological characterizations."
      explanation: This links tremor with dopaminergic neuronal loss as part of
        PD hallmark pathology, supporting the downstream relationship.
  - target: Bradykinesia
    evidence:
    - reference: PMID:17955331
      reference_title: "The Rotterdam Study: objectives and design update."
      supports: SUPPORT
      snippet: "Participants are screened in the baseline and follow-up examinations
        for cardinal signs of parkinsonism (resting tremor, rigidity, bradykinesia
        or impaired postural reflexes)."
      explanation: This establishes bradykinesia as a cardinal parkinsonian sign
        downstream of dopaminergic degeneration.
  - target: Rigidity
    evidence:
    - reference: PMID:17955331
      reference_title: "The Rotterdam Study: objectives and design update."
      supports: SUPPORT
      snippet: "Participants are screened in the baseline and follow-up examinations
        for cardinal signs of parkinsonism (resting tremor, rigidity, bradykinesia
        or impaired postural reflexes)."
      explanation: This identifies rigidity as a cardinal sign of parkinsonism
        consistent with dopaminergic neuron loss in PD.
  - target: Postural Instability
    evidence:
    - reference: PMID:17955331
      reference_title: "The Rotterdam Study: objectives and design update."
      supports: SUPPORT
      snippet: "Participants are screened in the baseline and follow-up examinations
        for cardinal signs of parkinsonism (resting tremor, rigidity, bradykinesia
        or impaired postural reflexes)."
      explanation: This supports impaired postural reflexes as a cardinal
        parkinsonian sign downstream of dopaminergic dysfunction.
  evidence:
  - reference: PMID:37048085
    reference_title: "Microglia Mediated Neuroinflammation in Parkinson's Disease."
    supports: SUPPORT
    snippet: "Tremor, shaking, movement problems, and difficulty with balance and
      coordination are among the hallmarks, and dopaminergic neuronal loss in substantia
      nigra pars compacta of the brain and aggregation of intracellular protein α-synuclein
      are the pathological characterizations."
    explanation: This review confirms that dopaminergic neuronal loss in the
      substantia nigra pars compacta is a pathological hallmark of Parkinson's
      disease, supporting the core mechanism of dopaminergic neuron
      degeneration.
- name: Alpha-Synuclein Aggregation
  description: >
    Misfolded alpha-synuclein protein accumulates to form Lewy bodies and
    Lewy neurites. These aggregates spread through the nervous system in a
    prion-like manner, contributing to neurodegeneration.
  biological_processes:
  - preferred_term: inclusion body assembly
    term:
      id: GO:0070841
      label: inclusion body assembly
  downstream:
  - target: Dopaminergic Neuron Loss
    evidence:
    - reference: PMID:38245249
      reference_title: "The pathogenesis of Parkinson's disease."
      supports: SUPPORT
      snippet: "Biochemical studies, investigation of transplanted neurons in patients
        with Parkinson's disease, and cell and animal model studies suggest that abnormal
        aggregation of α-synuclein and spreading of pathology between the gut, brainstem,
        and higher brain regions probably underlie the development and progression
        of Parkinson's disease."
      explanation: This indicates that α-synuclein aggregation drives disease
        development and progression, supporting downstream dopaminergic neuron
        loss.
  - target: Neuroinflammation
    evidence:
    - reference: PMID:36598534
      reference_title: "Role of α-synuclein in microglia: autophagy and phagocytosis balance neuroinflammation in Parkinson's disease."
      supports: SUPPORT
      snippet: "α-Syn is a crucial marker of PD, and its accumulation leads to microglia
        M1-like phenotype polarization, activation of NLRP3 inflammasomes, and impaired
        autophagy and phagocytosis in microglia."
      explanation: This links α-synuclein accumulation to microglial activation,
        supporting neuroinflammation as a downstream effect.
  evidence:
  - reference: PMID:38245249
    reference_title: "The pathogenesis of Parkinson's disease."
    supports: SUPPORT
    snippet: "Parkinson's disease is a progressive neurodegenerative condition associated
      with the deposition of aggregated α-synuclein."
    explanation: This authoritative Lancet review establishes that aggregated
      α-synuclein deposition is a defining feature of Parkinson's disease
      pathogenesis.
  - reference: PMID:38245249
    reference_title: "The pathogenesis of Parkinson's disease."
    supports: SUPPORT
    snippet: "Biochemical studies, investigation of transplanted neurons in patients
      with Parkinson's disease, and cell and animal model studies suggest that abnormal
      aggregation of α-synuclein and spreading of pathology between the gut, brainstem,
      and higher brain regions probably underlie the development and progression of
      Parkinson's disease."
    explanation: This provides direct evidence for the prion-like spreading
      mechanism of α-synuclein pathology across neural networks, supporting the
      mechanism of trans-neuronal propagation.
  - reference: PMID:36598534
    reference_title: "Role of α-synuclein in microglia: autophagy and phagocytosis balance neuroinflammation in Parkinson's disease."
    supports: SUPPORT
    snippet: "Parkinson's disease (PD) is the second most common neurodegenerative
      disease, and is characterized by accumulation of α-synuclein (α-syn)."
    explanation: Confirms that α-synuclein accumulation is a key pathological
      characterization of PD, reinforcing the central role of protein
      aggregation in disease pathology.
- name: Mitochondrial Dysfunction
  description: >
    Impaired mitochondrial function, particularly complex I deficiency,
    leads to oxidative stress and neuronal death. Multiple PD genes
    (PINK1, Parkin, DJ-1) regulate mitochondrial quality control.
  biological_processes:
  - preferred_term: mitochondrion organization
    term:
      id: GO:0007005
      label: mitochondrion organization
  downstream:
  - target: Dopaminergic Neuron Loss
    evidence:
    - reference: PMID:27911343
      reference_title: "PINK1, Parkin, and Mitochondrial Quality Control: What can we Learn about Parkinson's Disease Pathobiology?"
      supports: SUPPORT
      snippet: "For the past 30 years, mitochondrial dysfunction has been hypothesized
        to play a central role in the pathobiology of this devastating neurodegenerative
        disease."
      explanation: This supports mitochondrial dysfunction as a central driver
        of neurodegeneration in PD, consistent with dopaminergic neuron loss.
  evidence:
  - reference: PMID:38245249
    reference_title: "The pathogenesis of Parkinson's disease."
    supports: SUPPORT
    snippet: "At a cellular level, abnormal mitochondrial, lysosomal, and endosomal
      function can be identified in both monogenic and sporadic Parkinson's disease,
      suggesting multiple potential treatment approaches."
    explanation: This establishes that mitochondrial dysfunction is a common
      cellular feature across both genetic and sporadic forms of PD, supporting
      its central role in disease pathogenesis.
  - reference: PMID:25611507
    reference_title: "The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson's disease."
    supports: SUPPORT
    snippet: "Biochemical and genetic studies reveal that the products of two genes
      that are mutated in autosomal recessive parkinsonism, PINK1 and Parkin, normally
      work together in the same pathway to govern mitochondrial quality control, bolstering
      previous evidence that mitochondrial damage is involved in Parkinson's disease."
    explanation: This directly supports the role of PINK1 and Parkin genes in
      mitochondrial quality control and confirms that mitochondrial damage is
      involved in PD pathogenesis.
  - reference: PMID:27911343
    reference_title: "PINK1, Parkin, and Mitochondrial Quality Control: What can we Learn about Parkinson's Disease Pathobiology?"
    supports: SUPPORT
    snippet: "For the past 30 years, mitochondrial dysfunction has been hypothesized
      to play a central role in the pathobiology of this devastating neurodegenerative
      disease. The identifications of mutations in genes encoding PINK1 (PTEN-induced
      kinase 1) and Parkin (E3 ubiquitin ligase) in familial PD and their functional
      association with mitochondrial quality control provided further support to this
      hypothesis."
    explanation: This review confirms the long-standing central role of
      mitochondrial dysfunction in PD and validates the connection between
      PINK1/Parkin mutations and mitochondrial quality control defects.
- name: Neuroinflammation
  description: >
    Activated microglia and astrocytes contribute to neurodegeneration
    through release of pro-inflammatory cytokines and oxidative stress.
  cell_types:
  - preferred_term: Microglia
    term:
      id: CL:0000129
      label: microglial cell
  - preferred_term: Astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  downstream:
  - target: Dopaminergic Neuron Loss
    evidence:
    - reference: PMID:37048085
      reference_title: "Microglia Mediated Neuroinflammation in Parkinson's Disease."
      supports: SUPPORT
      snippet: "Neuroinflammation has emerged as an involving mechanism at the initiation
        and development of PD."
      explanation: This indicates neuroinflammation contributes to PD
        progression, supporting dopaminergic neuron loss downstream.
  evidence:
  - reference: PMID:38245249
    reference_title: "The pathogenesis of Parkinson's disease."
    supports: SUPPORT
    snippet: "Recent work has also highlighted maladaptive immune and inflammatory
      responses, possibly triggered in the gut, that accelerate the pathogenesis of
      Parkinson's disease."
    explanation: This establishes that maladaptive immune and inflammatory
      responses play an active role in accelerating PD pathogenesis, supporting
      the neuroinflammation mechanism.
  - reference: PMID:37048085
    reference_title: "Microglia Mediated Neuroinflammation in Parkinson's Disease."
    supports: SUPPORT
    snippet: "Neuroinflammation has emerged as an involving mechanism at the initiation
      and development of PD. It is a complex network of interactions comprising immune
      and non-immune cells in addition to mediators of the immune response. Microglia,
      the resident macrophages in the CNS, take on the leading role in regulating
      neuroinflammation and maintaining homeostasis."
    explanation: This directly supports the role of microglia-mediated
      neuroinflammation in PD initiation and progression, confirming the
      importance of microglial activation in disease pathology.
  - reference: PMID:36598534
    reference_title: "Role of α-synuclein in microglia: autophagy and phagocytosis balance neuroinflammation in Parkinson's disease."
    supports: SUPPORT
    snippet: "Neuroinflammation driven by microglia is an important pathological manifestation
      of PD. α-Syn is a crucial marker of PD, and its accumulation leads to microglia
      M1-like phenotype polarization, activation of NLRP3 inflammasomes, and impaired
      autophagy and phagocytosis in microglia."
    explanation: This links α-synuclein accumulation to microglial activation
      and pro-inflammatory M1 phenotype polarization, supporting the mechanism
      by which neuroinflammation contributes to neurodegeneration in PD.
- name: Autophagy-Lysosome Pathway Dysfunction
  description: >
    Impairment of the autophagy-lysosome pathway disrupts clearance of misfolded
    proteins including alpha-synuclein. Multiple PD genes (GBA, LRRK2, VPS35,
    ATP13A2) regulate lysosomal function, and their mutations impair protein
    degradation capacity leading to toxic protein accumulation.
  cell_types:
  - preferred_term: Dopaminergic Neuron
    term:
      id: CL:0000700
      label: dopaminergic neuron
  biological_processes:
  - preferred_term: Autophagy
    term:
      id: GO:0006914
      label: autophagy
  - preferred_term: Chaperone-mediated Autophagy
    term:
      id: GO:0061684
      label: chaperone-mediated autophagy
  downstream:
  - target: Alpha-Synuclein Aggregation
    evidence:
    - reference: PMID:31761667
      reference_title: "Autophagy lysosomal pathway dysfunction in Parkinson's disease; evidence from human genetics."
      supports: SUPPORT
      snippet: "α-synuclein, encoded by the SNCA gene, is degraded mainly by the ALP,
        and mutations/multiplications in SNCA may lead to impairment of chaperone
        mediated autophagy or other ALP functions."
      explanation: This shows that autophagy-lysosome pathway dysfunction
        impairs α-synuclein clearance, supporting aggregation downstream.
  - target: Dopaminergic Neuron Loss
    evidence:
    - reference: PMID:31761667
      reference_title: "Autophagy lysosomal pathway dysfunction in Parkinson's disease; evidence from human genetics."
      supports: SUPPORT
      snippet: "In recent years, multiple lines of evidence from human genetic and
        molecular studies have highlighted the importance of the autophagy lysosomal
        pathway (ALP) in Parkinson's disease (PD)."
      explanation: This supports ALP dysfunction as a key PD mechanism
        contributing to neuronal degeneration.
  evidence:
  - reference: PMID:31761667
    reference_title: "Autophagy lysosomal pathway dysfunction in Parkinson's disease; evidence from human genetics."
    supports: SUPPORT
    snippet: "In recent years, multiple lines of evidence from human genetic and molecular
      studies have highlighted the importance of the autophagy lysosomal pathway (ALP)
      in Parkinson's disease (PD). Genes such as GBA and LRRK2, which harbor some
      of the most common mutations associated with PD, have essential roles in the
      ALP."
    explanation: This review establishes the genetic basis for
      autophagy-lysosome dysfunction in PD, identifying key genes and their
      mechanistic roles.
- name: Gut-Brain Axis Dysfunction
  description: >
    Alterations in gut microbiota composition trigger intestinal inflammation
    and may initiate alpha-synuclein misfolding in enteric neurons. Pathological
    alpha-synuclein spreads from gut to brain via the vagus nerve, supporting
    the gut-first hypothesis of PD pathogenesis.
  cell_types:
  - preferred_term: Enteric Neuron
    term:
      id: CL:0000107
      label: autonomic neuron
  - preferred_term: Enteroendocrine Cell
    term:
      id: CL:0000164
      label: enteroendocrine cell
  biological_processes:
  - preferred_term: Inflammatory Response
    term:
      id: GO:0006954
      label: inflammatory response
  downstream:
  - target: Alpha-Synuclein Aggregation
    evidence:
    - reference: PMID:38245249
      reference_title: "The pathogenesis of Parkinson's disease."
      supports: SUPPORT
      snippet: "Biochemical studies, investigation of transplanted neurons in patients
        with Parkinson's disease, and cell and animal model studies suggest that abnormal
        aggregation of α-synuclein and spreading of pathology between the gut, brainstem,
        and higher brain regions probably underlie the development and progression
        of Parkinson's disease."
      explanation: This links gut-to-brain spread with α-synuclein aggregation,
        supporting this downstream effect.
  - target: Neuroinflammation
    evidence:
    - reference: PMID:38245249
      reference_title: "The pathogenesis of Parkinson's disease."
      supports: SUPPORT
      snippet: "Recent work has also highlighted maladaptive immune and inflammatory
        responses, possibly triggered in the gut, that accelerate the pathogenesis
        of Parkinson's disease."
      explanation: This supports gut-triggered immune responses as a driver of
        neuroinflammation in PD.
  - target: Constipation
    evidence:
    - reference: PMID:38098067
      reference_title: "Parkinson's disease and gut microbiota: from clinical to mechanistic and therapeutic studies."
      supports: SUPPORT
      snippet: "The typical symptomatology of PD includes motor symptoms; however,
        a range of nonmotor symptoms, such as intestinal issues, usually occur before
        the motor symptoms."
      explanation: This supports constipation and other intestinal symptoms as
        early gut-related manifestations in PD.
  evidence:
  - reference: PMID:38098067
    reference_title: "Parkinson's disease and gut microbiota: from clinical to mechanistic and therapeutic studies."
    supports: SUPPORT
    snippet: "Various microorganisms inhabiting the gastrointestinal tract can profoundly
      influence the physiopathology of the central nervous system through neurological,
      endocrine, and immune system pathways involved in the microbiota-gut-brain axis."
    explanation: This review establishes the gut microbiota-brain connection in
      PD pathophysiology.
  - reference: PMID:37449597
    reference_title: "Gut-microbiome-brain axis: the crosstalk between the vagus nerve, alpha-synuclein and the brain in Parkinson's disease."
    supports: SUPPORT
    snippet: "The vagus nerve, the main component of the parasympathetic nervous system,
      is involved in the regulation of immune response, digestion, heart rate, and
      control of mood."
    explanation: Establishes the vagus nerve as the key anatomical connection
      mediating gut-brain communication in PD.
- name: Oxidative Stress
  description: >
    Excessive reactive oxygen species from dopamine metabolism and mitochondrial
    dysfunction causes lipid peroxidation, protein carbonylation, and DNA damage.
    Dopamine auto-oxidation generates toxic quinones that preferentially damage
    substantia nigra neurons.
  cell_types:
  - preferred_term: Dopaminergic Neuron
    term:
      id: CL:0000700
      label: dopaminergic neuron
  biological_processes:
  - preferred_term: Response to Oxidative Stress
    term:
      id: GO:0006979
      label: response to oxidative stress
  - preferred_term: ROS Metabolic Process
    term:
      id: GO:0072593
      label: reactive oxygen species metabolic process
  downstream:
  - target: Mitochondrial Dysfunction
  - target: Dopaminergic Neuron Loss
  - target: Alpha-Synuclein Aggregation
  evidence:
  - reference: PMID:37303175
    reference_title: "Oxidative Stress and Dopaminergic Metabolism: A Major PD Pathogenic Mechanism and Basis of Potential Antioxidant Therapies."
    supports: SUPPORT
    snippet: "Reactive oxygen species (ROS)-induced oxidative stress triggers the
      vicious cycle leading to the degeneration of dopaminergic neurons in the nigra
      pars compacta."
    explanation: This review directly describes the mechanism by which oxidative
      stress drives dopaminergic neurodegeneration.
- name: Calcium Dysregulation
  description: >
    Substantia nigra dopaminergic neurons rely on L-type calcium channels (CaV1.3)
    for autonomous pacemaking, making them uniquely vulnerable to calcium-mediated
    toxicity. Disrupted calcium homeostasis in mitochondria, ER, and lysosomes
    contributes to oxidative stress and cell death.
  cell_types:
  - preferred_term: Dopaminergic Neuron
    term:
      id: CL:0000700
      label: dopaminergic neuron
  biological_processes:
  - preferred_term: Calcium Ion Homeostasis
    term:
      id: GO:0055074
      label: calcium ion homeostasis
  - preferred_term: Calcium Ion Transport
    term:
      id: GO:0070588
      label: calcium ion transmembrane transport
  downstream:
  - target: Mitochondrial Dysfunction
  - target: Oxidative Stress
  - target: Dopaminergic Neuron Loss
  evidence:
  - reference: PMID:35339179
    reference_title: "The Role of Voltage-Gated Calcium Channels in Basal Ganglia Neurodegenerative Disorders."
    supports: SUPPORT
    snippet: "Calcium (Ca2+) plays a central role in regulating many cellular processes
      and influences cell survival."
    explanation: This review establishes the fundamental role of calcium channel
      dysregulation in PD pathogenesis.
- name: Endoplasmic Reticulum Stress
  description: >
    Accumulation of misfolded proteins in the ER activates the unfolded protein
    response (UPR). Chronic ER stress overwhelms protective mechanisms, triggering
    apoptotic pathways. Alpha-synuclein aggregates and GBA mutations directly
    impair ER function.
  cell_types:
  - preferred_term: Dopaminergic Neuron
    term:
      id: CL:0000700
      label: dopaminergic neuron
  biological_processes:
  - preferred_term: ER Stress Response
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
  - preferred_term: Unfolded Protein Response
    term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
  downstream:
  - target: Autophagy-Lysosome Pathway Dysfunction
  - target: Dopaminergic Neuron Loss
  evidence:
  - reference: PMID:38026955
    reference_title: "Strategies targeting endoplasmic reticulum stress to improve Parkinson's disease."
    supports: SUPPORT
    snippet: "Accumulating evidence shows that endoplasmic reticulum (ER) stress occurring
      in the SNpc DA neurons is an early event in the development of PD."
    explanation: This review establishes ER stress as an early and central event
      in PD pathogenesis.
- name: Synaptic Dysfunction
  description: >
    Impaired synaptic vesicle recycling, particularly defects in clathrin-mediated
    endocytosis, represents an early feature of PD. Multiple PD genes (DNAJC6,
    SYNJ1, LRRK2) regulate synaptic vesicle trafficking, and their dysfunction
    leads to synaptic failure before overt neurodegeneration.
  cell_types:
  - preferred_term: Dopaminergic Neuron
    term:
      id: CL:0000700
      label: dopaminergic neuron
  biological_processes:
  - preferred_term: Synaptic Vesicle Cycle
    term:
      id: GO:0099504
      label: synaptic vesicle cycle
  - preferred_term: Synaptic Vesicle Endocytosis
    term:
      id: GO:0048488
      label: synaptic vesicle endocytosis
  downstream:
  - target: Dopaminergic Neuron Loss
  - target: Alpha-Synuclein Aggregation
  evidence:
  - reference: PMID:38595283
    reference_title: "Dysfunction of synaptic endocytic trafficking in Parkinson's disease."
    supports: SUPPORT
    snippet: "Notably, several of these genes are linked to the synaptic vesicle recycling
      process, particularly the clathrin-mediated endocytosis pathway. This suggests
      that impaired synaptic vesicle recycling might represent an early feature of
      Parkinson's disease"
    explanation: Establishes synaptic vesicle endocytosis dysfunction as an
      early feature of PD.
- name: Iron Accumulation and Ferroptosis
  description: >
    Abnormal iron deposition in the substantia nigra promotes ferroptosis, an
    iron-dependent form of cell death characterized by lipid peroxidation. Iron
    catalyzes Fenton reactions generating hydroxyl radicals, and dysregulated
    iron metabolism contributes to oxidative damage.
  cell_types:
  - preferred_term: Dopaminergic Neuron
    term:
      id: CL:0000700
      label: dopaminergic neuron
  biological_processes:
  - preferred_term: Iron Ion Homeostasis
    term:
      id: GO:0006879
      label: intracellular iron ion homeostasis
  - preferred_term: Ferroptosis
    term:
      id: GO:0097707
      label: ferroptosis
  downstream:
  - target: Oxidative Stress
  - target: Dopaminergic Neuron Loss
  evidence:
  - reference: PMID:39218077
    reference_title: "Ferroptosis in Parkinson's disease -- The iron-related degenerative disease."
    supports: SUPPORT
    snippet: "Parkinson's disease (PD) is a prevalent and advancing age-related neurodegenerative
      disorder, distinguished by the degeneration of dopaminergic neurons in the substantia
      nigra pars compacta (SNpc). Iron regional deposit in SNpc is a significant pathological
      characteristic of PD."
    explanation: This review establishes iron accumulation as a significant
      pathological characteristic and mechanistic driver of PD.
- name: Blood-Brain Barrier Dysfunction
  description: >
    Altered tight junction proteins, transporter dysfunction, and alpha-synuclein
    accumulation compromise BBB integrity. BBB breakdown allows infiltration of
    peripheral immune cells and blood-borne molecules, amplifying neuroinflammation.
  cell_types:
  - preferred_term: Brain Endothelial Cell
    term:
      id: CL:0002618
      label: endothelial cell of umbilical vein
  - preferred_term: Pericyte
    term:
      id: CL:0000669
      label: pericyte
  - preferred_term: Astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  biological_processes:
  - preferred_term: BBB Maintenance
    term:
      id: GO:0035633
      label: maintenance of blood-brain barrier
  - preferred_term: Vascular Permeability
    term:
      id: GO:0043114
      label: regulation of vascular permeability
  downstream:
  - target: Neuroinflammation
  - target: Dopaminergic Neuron Loss
  evidence:
  - reference: PMID:39075566
    reference_title: "Blood-brain barrier alterations and their impact on Parkinson's disease pathogenesis and therapy."
    supports: SUPPORT
    snippet: "There is increasing evidence for blood-brain barrier (BBB) alterations
      in Parkinson's disease (PD), the second most common neurodegenerative disorder
      with rapidly rising prevalence."
    explanation: This comprehensive 2024 review establishes BBB dysfunction as
      an emerging mechanism in PD pathogenesis.
phenotypes:
- name: Resting Tremor
  category: Neurological
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: Classic "pill-rolling" tremor at rest
  phenotype_term:
    preferred_term: Resting Tremor
    term:
      id: HP:0002322
      label: Resting tremor
  evidence:
  - reference: PMID:17955331
    reference_title: "The Rotterdam Study: objectives and design update."
    supports: SUPPORT
    snippet: "Participants are screened in the baseline and follow-up examinations
      for cardinal signs of parkinsonism (resting tremor, rigidity, bradykinesia or
      impaired postural reflexes)."
    explanation: This identifies resting tremor as a cardinal sign used to
      detect parkinsonism, supporting it as a core PD phenotype.
- name: Bradykinesia
  category: Neurological
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: Slowness of movement, required for diagnosis
  phenotype_term:
    preferred_term: Bradykinesia
    term:
      id: HP:0002067
      label: Bradykinesia
  evidence:
  - reference: PMID:17955331
    reference_title: "The Rotterdam Study: objectives and design update."
    supports: SUPPORT
    snippet: "Participants are screened in the baseline and follow-up examinations
      for cardinal signs of parkinsonism (resting tremor, rigidity, bradykinesia or
      impaired postural reflexes)."
    explanation: This lists bradykinesia among the cardinal signs of
      parkinsonism, supporting its central role in PD.
- name: Rigidity
  category: Neurological
  frequency: VERY_FREQUENT
  notes: Cogwheel or lead-pipe rigidity
  phenotype_term:
    preferred_term: Rigidity
    term:
      id: HP:0002063
      label: Rigidity
  evidence:
  - reference: PMID:17955331
    reference_title: "The Rotterdam Study: objectives and design update."
    supports: SUPPORT
    snippet: "Participants are screened in the baseline and follow-up examinations
      for cardinal signs of parkinsonism (resting tremor, rigidity, bradykinesia or
      impaired postural reflexes)."
    explanation: This confirms rigidity as a cardinal sign of parkinsonism
      relevant to PD.
- name: Postural Instability
  category: Neurological
  frequency: FREQUENT
  notes: Develops in later disease stages
  phenotype_term:
    preferred_term: Postural Instability
    term:
      id: HP:0002172
      label: Postural instability
  evidence:
  - reference: PMID:17955331
    reference_title: "The Rotterdam Study: objectives and design update."
    supports: SUPPORT
    snippet: "Participants are screened in the baseline and follow-up examinations
      for cardinal signs of parkinsonism (resting tremor, rigidity, bradykinesia or
      impaired postural reflexes)."
    explanation: This supports postural instability as a cardinal parkinsonian
      sign captured in PD assessments.
- name: Hyposmia
  category: Sensory
  frequency: FREQUENT
  notes: Often precedes motor symptoms by years
  phenotype_term:
    preferred_term: Hyposmia
    term:
      id: HP:0004409
      label: Hyposmia
  evidence:
  - reference: PMID:24136244
    reference_title: "Hyposmia: a possible biomarker of Parkinson's disease."
    supports: SUPPORT
    snippet: "Hyposmia, identified as reduced sensitivity to odor, is a common non-motor
      symptom of Parkinson's disease (PD) that antedates the typical motor symptoms
      by several years. It occurs in ∼90% of early-stage cases of PD."
    explanation: This establishes hyposmia as a highly prevalent prodromal
      symptom that precedes motor symptoms, supporting its importance as an
      early marker of PD.
- name: Constipation
  category: Gastrointestinal
  frequency: FREQUENT
  notes: Common non-motor symptom
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  evidence:
  - reference: PMID:7845407
    reference_title: "Anorectal manometry in the assessment of anorectal function in Parkinson's disease: a comparison with chronic idiopathic constipation."
    supports: SUPPORT
    snippet: "We investigated the role of anorectal manometry in evaluating constipation
      and anorectal function in 15 patients with Parkinson's disease (PD) and compared
      results with those of 9 patients with idiopathic constipation (IC) and 8 control
      (C) subjects."
    explanation: This study directly evaluates constipation in PD patients,
      supporting constipation as a common non-motor symptom.
- name: Depression
  category: Psychiatric
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  evidence:
  - reference: PMID:41301797
    reference_title: "Non-Motor Symptoms as Markers of Disease Severity in Parkinson's Disease: Associations Between Constipation, Depression, REM Sleep Behavior Disorder, and Motor Impairment."
    supports: SUPPORT
    snippet: "Depressive symptoms were similar across groups, but in prodromal PD,
      higher GDS scores were associated with worse UPDRS III scores (p = 0.02), as
      well as higher freezing and fall scores."
    explanation: This indicates depressive symptoms are present and clinically
      relevant in PD, supporting depression as a non-motor phenotype.
stages:
- name: "Stage 1: Unilateral Disease"
  description: >
    Symptoms are present on one side of the body only. Mild unilateral involvement
    with minimal or no functional impairment. Patients may exhibit resting tremor,
    rigidity, or bradykinesia on one limb or side. Daily activities are not
    significantly affected.
  evidence:
  - reference: PMID:27918765
    supports: SUPPORT
    snippet: "the Hoehn and Yahr scale, with the lowest grade indicating unilateral
      involvement with minimal or no functional impairment"
    explanation: This describes Stage 1 (the lowest grade) as unilateral involvement
      with minimal or no functional impairment.
  - reference: PMID:34461264
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Clinical findings indicate that LID typically only occurs following the
      progression of PD motor symptoms from the unilateral (Hoehn and Yahr (HY) Stage
      I) to the bilateral stage (HY Stage II)."
    explanation: This identifies Stage I as the unilateral phase of PD motor symptoms.
  notes: >
    Original Hoehn and Yahr staging scale from 1967 (PMID:6067254). A modified
    scale with 0.5 increments (Stages 1.5, 2.5) has been widely adopted but
    lacks formal clinimetric validation.
- name: "Stage 2: Bilateral Disease Without Balance Impairment"
  description: >
    Symptoms are present on both sides of the body or at the midline. Bilateral
    involvement without impairment of balance. Patients show bilateral tremor,
    rigidity, and bradykinesia but maintain normal postural reflexes and physical
    independence.
  evidence:
  - reference: PMID:34461264
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Clinical findings indicate that LID typically only occurs following the
      progression of PD motor symptoms from the unilateral (Hoehn and Yahr (HY) Stage
      I) to the bilateral stage (HY Stage II)."
    explanation: This identifies Stage II as the bilateral stage of PD motor symptom
      progression.
  - reference: PMID:15372591
    supports: SUPPORT
    snippet: "the scale fulfills at least some criteria for reliability and validity,
      especially for the midranges of the scale (Stages 2-4)."
    explanation: The MDS Task Force report validates the reliability of midrange
      stages (2-4) of the Hoehn and Yahr scale.
- name: "Stage 3: Bilateral Disease With Postural Instability"
  description: >
    Mild to moderate bilateral disease with early postural instability. The first
    sign of impaired righting reflexes appears. Patients remain physically
    independent in daily activities but have clinically evident balance impairment.
  evidence:
  - reference: PMID:20181069
    supports: SUPPORT
    snippet: "The modified Hoehn and Yahr scale was 3: mild to moderate bilateral disease;
      some postural instability; physically independent."
    explanation: This directly defines Stage 3 as mild to moderate bilateral disease
      with some postural instability while remaining physically independent.
  - reference: PMID:15372591
    supports: SUPPORT
    snippet: "Because the HY scale is weighted heavily toward postural instability as
      the primary index of disease severity, it does not capture completely impairments
      or disability from other motor features of PD and gives no information on nonmotor
      problems."
    explanation: This highlights that the Hoehn and Yahr scale weights postural
      instability as a primary severity index, providing context for why balance
      impairment becomes central at Stage 3.
- name: "Stage 4: Severe Disability, Still Ambulatory"
  description: >
    Fully developed, severely disabling disease. Patients remain ambulatory but
    have marked loss of independence in daily activities. More than half require
    assistance with most activities of daily living, despite retained ability to
    complete walk-based assessments.
  evidence:
  - reference: PMID:34125001
    supports: SUPPORT
    snippet: "Her disease severity was classified as Hoehn and Yahr stage 4. The
      unified Parkinson's disease rating scale (UPDRS) part 3, 10-m walk test (10MWT),
      timed up-and-go test (TUG), Berg balance scale (BBS), and 30-s chair stand
      test (30-s CST) were used for assessment before and after intervention."
    explanation: This stage 4 case report shows that advanced patients can remain
      ambulatory enough to perform walk-based assessments despite severe motor impairment.
  - reference: PMID:40162911
    supports: SUPPORT
    snippet: "In the H-Y Stage 4 group, more than half of the patients required
      assistance with most ADLs, except feeding and bowel control."
    explanation: This directly supports substantial dependence in daily activities
      as a defining functional feature of Stage 4 disease.
- name: "Stage 5: Wheelchair-Bound or Bedridden"
  description: >
    Patient is confined to wheelchair or bedridden unless aided. Complete
    dependence on caregivers for all activities. Represents the most severe
    stage of motor disability in Parkinson's disease.
  evidence:
  - reference: PMID:27918765
    supports: SUPPORT
    snippet: "the highest grade defining patients with complete confinement to wheelchair
      or bed."
    explanation: This directly defines Stage 5 (the highest grade) as complete
      confinement to wheelchair or bed.
genetic:
- name: SNCA
  association: Causative
  notes: Alpha-synuclein gene, autosomal dominant forms
  evidence:
  - reference: PMID:9197268
    reference_title: "Mutation in the alpha-synuclein gene identified in families with Parkinson's disease."
    supports: SUPPORT
    snippet: "A mutation was identified in the alpha-synuclein gene, which codes for
      a presynaptic protein thought to be involved in neuronal plasticity, in the
      Italian kindred and in three unrelated families of Greek origin with autosomal
      dominant inheritance for the PD phenotype."
    explanation: This landmark 1997 Science paper identified the first SNCA
      mutations in familial PD with autosomal dominant inheritance, establishing
      SNCA as a causative gene for Parkinson's disease.
- name: LRRK2
  association: Risk Factor
  notes: Most common genetic cause of late-onset PD
  evidence:
  - reference: PMID:19945904
    reference_title: "Worldwide frequency of G2019S LRRK2 mutation in Parkinson's disease: a systematic review."
    supports: SUPPORT
    snippet: "The LRRK2 G2019S mutation is the most frequent known cause of familial
      and sporadic Parkinson's disease."
    explanation: This systematic review establishes that LRRK2 G2019S is the
      most common genetic cause of both familial and sporadic PD, supporting its
      role as the major genetic risk factor.
- name: GBA
  association: Risk Factor
  notes: Glucocerebrosidase, major genetic risk factor
  evidence:
  - reference: PMID:30097731
    reference_title: "The Genetics of Dementia with Lewy Bodies: Current Understanding and Future Directions."
    supports: SUPPORT
    snippet: "DLB shares risk loci with AD, in the APOE E4 allele, and with PD, in
      variation at GBA and SNCA."
    explanation: This identifies GBA as a genetic risk locus shared with PD,
      supporting its role as a PD risk factor.
- name: PARK2
  association: Causative
  notes: Parkin gene, early-onset autosomal recessive
  evidence:
  - reference: PMID:25611507
    reference_title: "The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson's disease."
    supports: SUPPORT
    snippet: "Biochemical and genetic studies reveal that the products of two genes
      that are mutated in autosomal recessive parkinsonism, PINK1 and Parkin, normally
      work together in the same pathway to govern mitochondrial quality control, bolstering
      previous evidence that mitochondrial damage is involved in Parkinson's disease."
    explanation: This establishes Parkin (PARK2) as a gene mutated in autosomal
      recessive parkinsonism, supporting its causative role.
- name: PINK1
  association: Causative
  notes: Mitochondrial kinase, autosomal recessive
  evidence:
  - reference: PMID:25611507
    reference_title: "The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson's disease."
    supports: SUPPORT
    snippet: "Biochemical and genetic studies reveal that the products of two genes
      that are mutated in autosomal recessive parkinsonism, PINK1 and Parkin, normally
      work together in the same pathway to govern mitochondrial quality control, bolstering
      previous evidence that mitochondrial damage is involved in Parkinson's disease."
    explanation: This identifies PINK1 mutations in autosomal recessive
      parkinsonism, supporting its causative role in PD.
environmental:
- name: Pesticide Exposure
  notes: Rotenone and paraquat linked to increased risk
  evidence:
  - reference: PMID:15177059
    reference_title: "Occupational and environmental risk factors for Parkinson's disease."
    supports: SUPPORT
    snippet: "there is general agreement that smoking and exposure to pesticides affect
      the probability of developing PD."
    explanation: This review supports pesticide exposure as an environmental
      factor influencing PD risk.
- name: Rural Living
  notes: Associated with pesticide/herbicide exposure
  evidence:
  - reference: PMID:15177059
    reference_title: "Occupational and environmental risk factors for Parkinson's disease."
    supports: PARTIAL
    snippet: "While clear links to rural living, dietary factors, exposure to metals,
      head injury, and exposure to infectious diseases during childhood have not been
      established, there is general agreement that smoking and exposure to pesticides
      affect the probability of developing PD."
    explanation: This review notes that clear links to rural living are not
      established, indicating mixed evidence for this risk factor.
- name: Head Trauma
  notes: Possible risk factor
  evidence:
  - reference: PMID:36781627
    reference_title: "Traumatic brain injury and risk of Parkinson's disease: a meta-analysis."
    supports: SUPPORT
    snippet: "The risk ratio of TBI among PD and controls by a combination of 15 studies
      using a random-effect model was 1.48 (95% CI 1.22-1.74)."
    explanation: This meta-analysis supports head trauma (TBI) as a risk factor
      for developing PD.
treatments:
- name: Levodopa/Carbidopa
  description: Gold standard treatment, replaces dopamine precursor.
  evidence:
  - reference: PMID:27577098
    reference_title: "Current and experimental treatments of Parkinson disease: A guide for neuroscientists."
    supports: SUPPORT
    snippet: "The symptomatic treatment of the motor symptoms of Parkinson disease
      (PD) has been constantly optimized using pharmacotherapy (L-Dopa, several dopamine
      agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase
      (COMT), and amantadine), deep brain stimulation, and physiotherapy."
    explanation: This review identifies L-Dopa as a core pharmacotherapy for PD
      motor symptoms.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: levodopa
      term:
        id: CHEBI:15765
        label: L-dopa
    - preferred_term: carbidopa
      term:
        id: CHEBI:3395
        label: carbidopa
- name: Dopamine Agonists
  description: Directly stimulate dopamine receptors.
  evidence:
  - reference: PMID:27577098
    reference_title: "Current and experimental treatments of Parkinson disease: A guide for neuroscientists."
    supports: SUPPORT
    snippet: "The symptomatic treatment of the motor symptoms of Parkinson disease
      (PD) has been constantly optimized using pharmacotherapy (L-Dopa, several dopamine
      agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase
      (COMT), and amantadine), deep brain stimulation, and physiotherapy."
    explanation: This review identifies dopamine agonists as part of standard
      pharmacotherapy for PD.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
- name: MAO-B Inhibitors
  description: Prevent dopamine breakdown (selegiline, rasagiline).
  evidence:
  - reference: PMID:27577098
    reference_title: "Current and experimental treatments of Parkinson disease: A guide for neuroscientists."
    supports: SUPPORT
    snippet: "The symptomatic treatment of the motor symptoms of Parkinson disease
      (PD) has been constantly optimized using pharmacotherapy (L-Dopa, several dopamine
      agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase
      (COMT), and amantadine), deep brain stimulation, and physiotherapy."
    explanation: This review lists MAO-B inhibitors among standard PD
      pharmacotherapies.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
- name: COMT Inhibitors
  description: Extend levodopa duration (entacapone).
  evidence:
  - reference: PMID:27577098
    reference_title: "Current and experimental treatments of Parkinson disease: A guide for neuroscientists."
    supports: SUPPORT
    snippet: "The symptomatic treatment of the motor symptoms of Parkinson disease
      (PD) has been constantly optimized using pharmacotherapy (L-Dopa, several dopamine
      agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase
      (COMT), and amantadine), deep brain stimulation, and physiotherapy."
    explanation: This review lists COMT inhibitors among standard PD
      pharmacotherapies.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
- name: Deep Brain Stimulation
  description: Surgical therapy for advanced motor fluctuations.
  evidence:
  - reference: PMID:27577098
    reference_title: "Current and experimental treatments of Parkinson disease: A guide for neuroscientists."
    supports: SUPPORT
    snippet: "The symptomatic treatment of the motor symptoms of Parkinson disease
      (PD) has been constantly optimized using pharmacotherapy (L-Dopa, several dopamine
      agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase
      (COMT), and amantadine), deep brain stimulation, and physiotherapy."
    explanation: This review identifies deep brain stimulation as a standard
      symptomatic therapy for PD.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
- name: Physical Therapy
  description: Maintains mobility and reduces fall risk.
  evidence:
  - reference: PMID:27577098
    reference_title: "Current and experimental treatments of Parkinson disease: A guide for neuroscientists."
    supports: SUPPORT
    snippet: "The symptomatic treatment of the motor symptoms of Parkinson disease
      (PD) has been constantly optimized using pharmacotherapy (L-Dopa, several dopamine
      agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase
      (COMT), and amantadine), deep brain stimulation, and physiotherapy."
    explanation: This review lists physiotherapy as part of symptomatic
      treatment for PD.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
datasets:
# Parkinson's Disease Gut Microbiome Studies
- accession: sra:PRJNA834801
  title: Large-scale metagenomics of Parkinson's disease gut microbiome
  description: >-
    Shotgun metagenomics from the NeuroGenetics Research Consortium (NGRC)
    with over 30% of species, genes and pathways showing altered abundances
    in PD. Identified polymicrobial clusters and competitive relationships.
  organism:
    preferred_term: human gut metagenome
    term:
      id: NCBITaxon:408170
      label: human gut metagenome
  data_type: WGS
  sample_types:
  - preferred_term: fecal sample
    term:
      id: OBI:0002503
      label: feces specimen
    tissue_term:
      preferred_term: feces
      term:
        id: UBERON:0001988
        label: feces
  conditions:
  - Parkinson's disease
  - healthy controls
  publication: PMID:36357667
  notes: Nature Communications 2022 - largest PD metagenomics to date
  evidence:
  - reference: PMID:37449597
    reference_title: "Gut-microbiome-brain axis: the crosstalk between the vagus nerve, alpha-synuclein and the brain in Parkinson's disease."
    supports: SUPPORT
    snippet: "This critical review of the literature shows that there is a close link
      between the microbiome, the gut, and the brain in Parkinson's disease."
    explanation: This supports the relevance of gut microbiome datasets to PD
      mechanisms.

- accession: sra:PRJNA782492
  title: Multi-omics analysis of PD gut microbiome gene expression
  description: >-
    Integrated metagenomics and metatranscriptomics analyzing microbiome gene
    co-expression networks in Parkinson's disease. Observed significant
    depletion of hub genes in PD patients.
  organism:
    preferred_term: human gut metagenome
    term:
      id: NCBITaxon:408170
      label: human gut metagenome
  data_type: WGS
  sample_types:
  - preferred_term: fecal sample
    term:
      id: OBI:0002503
      label: feces specimen
    tissue_term:
      preferred_term: feces
      term:
        id: UBERON:0001988
        label: feces
  conditions:
  - Parkinson's disease
  - healthy controls
  notes: npj Biofilms and Microbiomes 2025 - multi-omics approach
  evidence:
  - reference: PMID:37449597
    reference_title: "Gut-microbiome-brain axis: the crosstalk between the vagus nerve, alpha-synuclein and the brain in Parkinson's disease."
    supports: SUPPORT
    snippet: "This critical review of the literature shows that there is a close link
      between the microbiome, the gut, and the brain in Parkinson's disease."
    explanation: This supports the relevance of gut microbiome datasets to PD
      mechanisms.

- accession: sra:PRJNA808166
  title: Longitudinal gut microbiome in Parkinson's disease
  description: >-
    Longitudinal study investigating gut microbiome changes in PD patients
    and impact of device-assisted therapies. Tracks microbiome alterations
    with disease progression.
  organism:
    preferred_term: human gut metagenome
    term:
      id: NCBITaxon:408170
      label: human gut metagenome
  sample_types:
  - preferred_term: fecal sample
    term:
      id: OBI:0002503
      label: feces specimen
    tissue_term:
      preferred_term: feces
      term:
        id: UBERON:0001988
        label: feces
  conditions:
  - Parkinson's disease baseline
  - Parkinson's disease follow-up
  notes: Frontiers Aging Neuroscience 2022 - longitudinal design
  evidence:
  - reference: PMID:37449597
    reference_title: "Gut-microbiome-brain axis: the crosstalk between the vagus nerve, alpha-synuclein and the brain in Parkinson's disease."
    supports: SUPPORT
    snippet: "This critical review of the literature shows that there is a close link
      between the microbiome, the gut, and the brain in Parkinson's disease."
    explanation: This supports the relevance of gut microbiome datasets to PD
      mechanisms.

- accession: sra:PRJNA530401
  title: PD gut microbiome meta-analysis cohort
  description: >-
    Metagenomic sequencing data from PD patients and controls contributing
    to cross-cohort meta-analyses. Identified alterations linked to
    intestinal inflammation including reduced butyrate producers.
  organism:
    preferred_term: human gut metagenome
    term:
      id: NCBITaxon:408170
      label: human gut metagenome
  data_type: WGS
  sample_types:
  - preferred_term: fecal sample
    term:
      id: OBI:0002503
      label: feces specimen
    tissue_term:
      preferred_term: feces
      term:
        id: UBERON:0001988
        label: feces
  conditions:
  - Parkinson's disease
  - healthy controls
  notes: npj Parkinson's Disease 2021 - meta-analysis contributing cohort
  evidence:
  - reference: PMID:37449597
    reference_title: "Gut-microbiome-brain axis: the crosstalk between the vagus nerve, alpha-synuclein and the brain in Parkinson's disease."
    supports: SUPPORT
    snippet: "This critical review of the literature shows that there is a close link
      between the microbiome, the gut, and the brain in Parkinson's disease."
    explanation: This supports the relevance of gut microbiome datasets to PD
      mechanisms.

- accession: metabolights:MTBLS2266
  title: Metabolomics of sebum reveals lipid dysregulation in Parkinson's
    disease
  description: >-
    LC-MS sebum metabolomics in Parkinson's disease, including drug-naive and
    medicated cohorts, compared with well-matched controls to identify lipid
    pathway alterations.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: METABOLOMICS
  sample_count: 274
  conditions:
  - Parkinson's disease
  - drug-naive Parkinson's disease
  - medicated Parkinson's disease
  - healthy controls
  publication: PMID:33707447
  findings:
  - statement: Sebum metabolomics in PD shows alterations in lipid metabolism
      pathways, including the carnitine shuttle, sphingolipid metabolism,
      arachidonic acid metabolism and fatty acid biosynthesis.
    evidence:
    - reference: metabolights:MTBLS2266
      supports: SUPPORT
      snippet: "Pathway enrichment analysis shows alterations in lipid metabolism
        related to the carnitine shuttle, sphingolipid metabolism, arachidonic acid
        metabolism and fatty acid biosynthesis."
      explanation: The dataset description reports lipid pathway alterations
        detected in sebum metabolomics for PD.
  - statement: LC-MS profiling of 274 participants detected metabolites
      predictive of PD phenotype.
    evidence:
    - reference: metabolights:MTBLS2266
      supports: SUPPORT
      snippet: "We used liquid chromatography-mass spectrometry (LC-MS) to analyse
        274 samples from participants (80 drug naïve PD, 138 medicated PD and 56 well
        matched control subjects) and detected metabolites that could predict PD phenotype."
      explanation: The dataset description specifies LC-MS profiling and the
        PD/control cohort sizes.
  evidence:
  - reference: metabolights:MTBLS2266
    supports: SUPPORT
    snippet: "Here, we use a metabolomics profiling approach to identify changes to
      lipids in PD observed in sebum, a non-invasively available biofluid."
    explanation: Establishes that the dataset focuses on PD sebum metabolomics.
  notes: Metabolomics profiling of sebum as a non-invasive biofluid for PD.

- accession: metabolights:MTBLS10743
  title: Metabolomic Changes in Idiopathic and GBA1 Parkinson’s Disease
  description: >-
    Mass spectrometry metabolomics comparing idiopathic Parkinson's disease and
    GBA1-associated Parkinson's disease cohorts with controls.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: METABOLOMICS
  conditions:
  - idiopathic Parkinson's disease
  - GBA1-associated Parkinson's disease
  - healthy controls
  findings:
  - statement: Metabolomic signatures differ between GBA1-PD and idiopathic PD
      in sebum and serum with good specificity and sensitivity.
    evidence:
    - reference: metabolights:MTBLS10743
      supports: SUPPORT
      snippet: "Differences in metabolomic signatures were seen between ... GBA1-PD
        and iPD in sebum and serum with good specificity and sensitivity."
      explanation: The dataset description reports discriminative metabolomic
        signatures between GBA1-PD and idiopathic PD.
  - statement: Serum pathways implicated include sphingolipid metabolism, amino
      sugar metabolism and amino acid pathways, while sebum features are
      hypothesised to be lipid degradation products.
    evidence:
    - reference: metabolights:MTBLS10743
      supports: SUPPORT
      snippet: "Significant pathways in serum included sphingolipid metabolism, amino
        sugar metabolism and amino acid pathways, whereas significant features between
        groups in sebum are hypothesised to be lipid degradation products."
      explanation: The dataset description lists pathway-level differences in
        serum and hypothesized lipid degradation products in sebum.
  evidence:
  - reference: metabolights:MTBLS10743
    supports: SUPPORT
    snippet: "Here, we use mass spectrometry based metabolomics to analyse serum and
      sebum samples from 50 genotyped participants and find differences in lipid and
      sugar regulation, oxidative stress and the production of amino acids and neurotransmitters
      which distinguish ... GBA1-PD from iPD."
    explanation: Establishes the dataset's serum and sebum metabolomics design
      distinguishing GBA1-PD from idiopathic PD.
  notes: Preprint dataset describing metabolic changes in idiopathic vs GBA1 PD.

# CELLxGENE - Multi-region single nucleus PD atlas
- accession: "cellxgene:d5d0df8f-4eee-49d8-a221-a288f50a1590"
  title: A multi-region single nucleus transcriptomic atlas of Parkinson's disease
  description: >-
    Single-nucleus RNA-seq atlas of Parkinson's disease spanning multiple brain
    regions, providing cell-type-resolved transcriptomic profiles of dopaminergic
    neurons and glial populations in PD and healthy controls.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_types:
  - preferred_term: brain tissue
    tissue_term:
      preferred_term: brain
      term:
        id: UBERON:0000955
        label: brain
  conditions:
  - Parkinson's disease
  - healthy controls
  publication: PMID:39317733
  notes: CZI CELLxGENE collection. DOI 10.1038/s41597-024-04117-y. Multi-region snRNA-seq atlas enabling virtual cell model training on PD-relevant cell states.

computational_models:
- name: Alpha-Synuclein Aggregation BST Model
  description: >
    Biochemical Systems Theory (BST) model of alpha-synuclein aggregation kinetics
    in dopaminergic neurons. Integrates dopamine metabolism, ubiquitin-proteasome
    system, and lysosomal degradation pathways. Simulates effects of oxidative
    stress and proteasome inhibition on synuclein accumulation.
  model_type: KINETIC
  repository_url: https://www.ebi.ac.uk/biomodels/BIOMD0000000575
  model_id: BIOMD0000000575
  publication: PMID:19136028
  notes: First comprehensive kinetic model of PD-related protein aggregation
- name: Whole Dopaminergic Neuron SBML Model
  description: >
    Large-scale Systems Biology Markup Language (SBML) model of dopaminergic
    neuron containing 139 reactions and 111 metabolites. Captures dopamine
    synthesis, vesicular storage, release, reuptake, and degradation alongside
    mitochondrial function and oxidative stress.
  model_type: KINETIC
  repository_url: https://www.ebi.ac.uk/biomodels/MODEL1302200000
  model_id: MODEL1302200000
  publication: PMID:24196439
  model_format: SBML
  notes: Enables simulation of drug effects on dopaminergic neurotransmission
- name: Basal Ganglia Spiking Neural Network
  description: >
    Computational model of the basal ganglia circuit capturing dopamine-modulated
    dynamics between striatum, globus pallidus, subthalamic nucleus, and
    substantia nigra. Simulates pathological beta-band oscillations and motor
    dysfunction in PD.
  model_type: PHYSIOLOGICAL
  publication: PMID:29666208
  notes: Models circuit-level effects of dopamine depletion and DBS therapy
- name: Alpha-Synuclein Prion-like Spreading Model
  description: >
    Network diffusion model simulating prion-like propagation of misfolded
    alpha-synuclein through brain connectome. Uses graph-theoretical approach
    to predict spatial patterns of neurodegeneration from initial seeding sites.
  model_type: AGENT_BASED
  notes: Predicts Braak staging patterns from connectivity-based spreading
references:
- reference: DOI:10.2147/ndt.s540718
  title: Updates on Parkinson’s Disease
  findings: []
- reference: DOI:10.3389/fnagi.2025.1617106
  title: 'Understanding Parkinson’s disease: current trends and its multifaceted complications'
  findings: []
- reference: DOI:10.3390/cells14151161
  title: 'Parkinson’s Disease: Bridging Gaps, Building Biomarkers, and Reimagining
    Clinical Translation'
  findings: []
- reference: DOI:10.3390/ijms25137183
  title: 'A Comprehensive Approach to Parkinson’s Disease: Addressing Its Molecular,
    Clinical, and Therapeutic Aspects'
  findings: []