name: Parkinson's Disease
creation_date: '2025-12-18T17:01:35Z'
updated_date: '2026-02-27T22:30:31Z'
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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:0055072
label: iron ion homeostasis
- preferred_term: Ferroptosis
term:
id: GO:0097707
label: ferroptotic cell death
downstream:
- target: Oxidative Stress
- target: Dopaminergic Neuron Loss
evidence:
- reference: PMID:39218077
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
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
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
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
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
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
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
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
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.
genetic:
- name: SNCA
association: Causative
notes: Alpha-synuclein gene, autosomal dominant forms
evidence:
- reference: PMID:9197268
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
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
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
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
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
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
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
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
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: NCIT:C611
label: Levodopa
- preferred_term: carbidopa
term:
id: CHEBI:3395
label: carbidopa
- name: Dopamine Agonists
description: Directly stimulate dopamine receptors.
evidence:
- reference: PMID:27577098
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
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
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
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
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
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
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
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
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.
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: []