Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Autosomal dominant striatal neurodegeneration. Core disease mechanisms, mo...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Huntington’s Disease and Striatal Signaling

• Authors: E. Roze, Emma N Cahill, E. Martin, C. Bonnet, P. Vanhoutte et al.
• Year: 2011
• Venue: Frontiers in Neuroanatomy
• URL: https://www.semanticscholar.org/paper/d038dd048bf659ae00bb3f1af31c4b8f83be148f
• DOI: 10.3389/fnana.2011.00055
• PMID: 22007160
• PMCID: 3188786
• Citations: 47
• Influential citations: 1
• Summary: One important characteristic of HD is the striatal vulnerability to neurodegeneration, despite similar expression of the protein in other brain areas, which means patients could theoretically benefit from therapy at early stages of the disease.
• Evidence snippets:
• Snippet 1 (score: 0.532) > Huntington’s Disease (HD) is the most frequent neurodegenerative disease caused by an expansion of polyglutamines (CAG). The main clinical manifestations of HD are chorea, cognitive impairment, and psychiatric disorders. The transmission of HD is autosomal dominant with a complete penetrance. HD has a single genetic cause, a well-defined neuropathology, and informative pre-manifest genetic testing of the disease is available. Striatal atrophy begins as early as 15 years before disease onset and continues throughout the period of manifest illness. Therefore, patients could theoretically benefit from therapy at early stages of the disease. One important characteristic of HD is the striatal vulnerability to neurodegeneration, despite similar expression of the protein in other brain areas. Aggregation of the mutated Huntingtin (HTT), impaired axonal transport, excitotoxicity, transcriptional dysregulation as well as mitochondrial dysfunction, and energy deficits, are all part of the cellular events that underlie neuronal dysfunction and striatal death. Among these non-exclusive mechanisms, an alteration of striatal signaling is thought to orchestrate the downstream events involved in the cascade of striatal dysfunction.

[2] Basic Science in Movement Disorders: Fueling the Engine of Translation into Clinical Practice

• Authors: T. Outeiro, L. Kalia, E. Bézard, Juan E. Ferrario, Chin-Hsien Lin et al.
• Year: 2024
• Venue: Movement Disorders
• URL: https://www.semanticscholar.org/paper/5d1128a1ddfe4eb0758997f4f948f89befa432a9
• DOI: 10.1002/mds.29802
• PMID: 38576081
• Citations: 1
• Summary: How basic science is important for understanding disease mechanisms, disease prevention, disease diagnosis, development of novel therapies and to establish the basis for personalized medicine is provided.
• Evidence snippets:
• Snippet 1 (score: 0.519) > Understanding movement disorders' basic mechanisms is the only road for rationalizing targeted therapeutics.In this context, basic research helps identify specific molecular pathways, neurotransmitter systems, brain circuitries, and genetic factors involved in disease.This combined knowledge forms the basis for developing novel drugs, gene and cell replacement therapies, and other interventions aimed at modifying disease progression, alleviating symptoms, and improving patients' quality of life.Neurodegenerative diseases such as Huntington's disease (HD) tend now to be considered as neurodevelopmental disorders, eventually provoking neurodegeneration. 34Multiple strategies have recently been applied to the development of targeted therapy for HD, including antisense oligonucleotides which would not be possible without the basic science understanding of RNA silencing. 35For PD, the first large clinical trials targeting αSyn 36,37 with many expected over the upcoming years, are all based on more than 25 years of basic science research focused on the role of αSyn in PD. > Importantly, the design of clinical trials is increasingly guided by our understanding of the underlying pathobiology of disease.While there have been numerous successes for symptomatic therapies in movement disorders, there have been few thus far for diseasemodifying therapies.Regardless, negative clinical trials are valuable in our understanding of the basic mechanisms of disease and, in this context, the back-and-forth between the bench and the beside should continue as a major goal in the field.Advances in clinical design are anticipated to accelerate the translation from innovative basic science discoveries to the actual clinical testing.

[3] Thalamostriatal degeneration contributes to dystonia and cholinergic interneuron dysfunction in a mouse model of Huntington’s disease

• Authors: Gabriel Crevier-Sorbo, V. Rymar, Raphael Crevier-Sorbo, A. Sadikot
• Year: 2020
• Venue: Acta Neuropathologica Communications
• URL: https://www.semanticscholar.org/paper/6afbaf799cd439646f17089ea0e389a02559a7e1
• DOI: 10.1186/s40478-020-0878-0
• PMID: 32033588
• PMCID: 7007676
• Citations: 13
• Summary: Results using the R6/2 mouse model of HD indicate that neurons of the parafascicular nucleus (PF), the main source of TS afferents, degenerate at an early stage and contributes to degeneration of striatal neuronal subtypes, and behavioural experiments demonstrate that the TS system and striatal cholinergic interneurons are key motor-network structures involved in the pathogenesis of dystonia.
• Evidence snippets:
• Snippet 1 (score: 0.519) > Huntington’s disease (HD) is an autosomal dominant trinucleotide repeat disorder characterized by choreiform movements, dystonia and striatal neuronal loss. Amongst multiple cellular processes, abnormal neurotransmitter signalling and decreased trophic support from glutamatergic cortical afferents are major mechanisms underlying striatal degeneration. Recent work suggests that the thalamostriatal (TS) system, another major source of glutamatergic input, is abnormal in HD although its phenotypical significance is unknown. We hypothesized that TS dysfunction plays an important role in generating motor symptoms and contributes to degeneration of striatal neuronal subtypes. Our results using the R6/2 mouse model of HD indicate that neurons of the parafascicular nucleus (PF), the main source of TS afferents, degenerate at an early stage. PF lesions performed prior to motor dysfunction or striatal degeneration result in an accelerated dystonic phenotype and are associated with premature loss of cholinergic interneurons. The progressive loss of striatal medium spiny neurons and parvalbumin-positive interneurons observed in R6/2 mice is unaltered by PF lesions. Early striatal cholinergic ablation using a mitochondrial immunotoxin provides evidence for increased cholinergic vulnerability to cellular energy failure in R6/2 mice, and worsens the dystonic phenotype. The TS system therefore contributes to trophic support of striatal interneuron subtypes in the presence of neurodegenerative stress, and TS deafferentation may be a novel cell non-autonomous mechanism contributing to the pathogenesis of HD. Furthermore, behavioural experiments demonstrate that the TS system and striatal cholinergic interneurons are key motor-network structures involved in the pathogenesis of dystonia. This work suggests that treatments aimed at rescuing the TS system may preserve important elements of striatal structure and function and provide symptomatic relief in HD.

[4] Oxidative Stress in Genetic Mouse Models of Parkinson's Disease

• Authors: M. Varçin, Eduard Bentea, Y. Michotte, S. Sarre
• Year: 2012
• Venue: Oxidative Medicine and Cellular Longevity
• URL: https://www.semanticscholar.org/paper/9dfda510fe4b7b60d72899825206ac72b2265109
• DOI: 10.1155/2012/624925
• PMID: 22829959
• PMCID: 3399377
• Citations: 91
• Influential citations: 3
• Summary: Basic mechanisms of oxidative stress, the cellular antioxidant machinery, and the main sources of cellular oxidative stress are reviewed, and attention is given to the complex interaction between oxidative stress and other prominent pathogenic pathways in Parkinson's disease, such as mitochondrial dysfunction and neuroinflammation.
• Evidence snippets:
• Snippet 1 (score: 0.517) > There are also nondopaminergic neurons affected in PD, leading to more wide-spread neuronal changes that cause a complex and heterogeneous clinical picture [7,9]. Recently, Braak and colleagues hypothesized a six-stage pathological process in which PD pathology emerges in the olfactory bulb and the dorsal motor nucleus of the vagal nerve and only in later stages extends to the midbrain and other brainstem regions [10,11]. Current therapies of PD are symptomatic, targeting the lack of DA in the striatum with DA replacement strategies. Although these therapies provide symptomatic relief at the beginning, they become gradually inefficient as the disease progresses. Therefore, there is an urgent need of therapeutic strategies that can tackle the disease progression [12]. > Despite the fact that PD has long been considered as a non-genetic disorder of sporadic origin, research performed during the past decade has led to the identification of genes linked to rare monogenic forms of PD. This resulted in the identification of 16 "PARK" loci, with the autosomal dominant genes SNCA (PARK1/4), and LRRK2 (PARK8), and the autosomal recessive genes parkin (PARK2), DJ-1 (PARK7), and PINK1 (PARK6) being the most common ones [2,3,5]. Although monogenic forms account for <10% of PD cases, these genes also play a role in the much more common sporadic form of the disease [5]. Unraveling the molecular mechanisms underlying the familial forms of PD will contribute to our understanding of sporadic PD, since both share clinical and neuropathological features [5]. Moreover, several cellular abnormalities which may underlie the neurodegeneration displayed in sporadic PD, such as mitochondrial dysfunction, oxidative stress, excitotoxicity, proteasomal stress, neuroinflammation, and protein aggregation, are also associated with mutations in the familial PD genes [13,14]. > Multiple animal models have been developed in order to study the pathogenesis and progression of PD and to test potential therapeutic strategies [15].

[5] A Journey through Huntington's Disease: Exploring Genetics, Neurobiology, and Therapeutic Advances

• Authors: Sandeep Dey, Shreyas Katta, S. Suresh, Janhvi Mishra
• Year: 2024
• Venue: International Journal For Multidisciplinary Research
• URL: https://www.semanticscholar.org/paper/735574648bec278cf15dc25fd5f1d735afaf6ae6
• DOI: 10.36948/ijfmr.2024.v06i03.19194
• Summary: The clinical features, ethics, and neurobiology of HD are discussed and the exciting approaches being employed today to advance understanding of underlying mechanisms in an effort to develop therapies that would delay the onset and slow progression of this disease are reviewed.
• Evidence snippets:
• Snippet 1 (score: 0.513) > Also, we present a modern view on the molecular biology of HD as a representative of the group of polyglutamine diseases, with an emphasis on conformational changes of mutant huntingtin, disturbances in its cellular processing, and proteolytic stress in degenerating neurons. > The main pathogenetic mechanisms of neurodegeneration in HD are discussed in detail, such as autophagy, impaired mitochondrial biogenesis, lysosomal dysfunction, organelle and protein transport, inflammation, oxidative stress, and transcription factor modulation. However, other unravelling mechanisms are still unknown. This practical and brief review summarises some of the currently known functions of the wild-type huntingtin protein and the recent findings related to the mechanisms involved in HD pathogenesis. Cellular mechanisms implicated in HD pathogenesis: The major mechanisms associated with HD pathogenesis are depicted here. The schematic shows a presynaptic neuron and a postsynaptic neuron flanked by two astrocytes. Huntingtin gene(HTT) itself is depicted as a "solenoid," based on the presumed folding due to its HEAT repeats. The mechanisms depicted are multimerization of mHtt-containing complexes, transcriptional modulation, ER-Golgi stress pathways, mitochondria and energy homeostasis, microtubular dynamics, endocytic and vesicular trafficking dynamics, autophagy, and synaptic signalling mechanisms. mHTT(mutant HTT protein). Traditionally, therapeutic approaches to HD have included compounds developed for psychiatric indications based on the affected neuronal circuitry: the frontal and motor corticostriatal circuits. None of these were initially developed for the treatment of HD. In this review we focus on the cellular and biological pathways affected by mutant HTT (mHTT) and the current status of associated drug discovery efforts. We also emphasise the need for further clinical research to validate existing hypotheses, which are mostly derived from animal studies and postmortem human tissues. It is generally accepted that most candidate therapeutics fail due to lack of efficacy in pivotal clinical studies.

[6] Toward a new nosology of neurodegenerative diseases

• Authors: M. Menéndez-González
• Year: 2023
• Venue: Alzheimer's & Dementia
• URL: https://www.semanticscholar.org/paper/4407f839d31ee6cbf707ee1aab7b9b0e613cc09a
• DOI: 10.1002/alz.13041
• PMID: 36960767
• Citations: 10
• Summary: This article aims to prompt a change in how NDD is diagnosed and classify, drafting a general scheme for a new nosology based on a tridimensional classification based on three axes: etiology or pathogenic mechanism, pathology markers and molecular biomarkers, anatomic–clinical; and three hierarchical levels of etiology.
• Evidence snippets:
• Snippet 1 (score: 0.513) > In spite of these shared alterations, the eight cellular dysfunctions were more or less associated with the identifiable pathologies in the brain characteristic of each disease. 36 Thus, changes in cellular pathways and cellular processes may be shared by multiple NDDs (and even by some diseases today considered psychiatric 37 ) driving distinctive anatomic-clinical features. Though more studies will be needed to better understand the processes involved, these common factors may be the initial seeds that later develop into each of the distinct CNS disorders, while the mechanisms responsible for them germinate into diverse diseases and symptomologies, attacking different regions of the brain. 38 e characteristic clinical picture for each NDD consists of a variable combination of cognitive, motor, and neuropsychiatric symptoms at the core, with a long list of other potentially associated symptoms. > These phenotypes are the "classic" forms of the disease, that is, as originally described (eponyms). Thus, traditional methods of describing and classifying NDDs are based on the original clinicopathological concept; that is, a distinct clinical profile in combination with "signature" pathological lesions. This system was used to describe the first cases of AD, 39 Pick's disease (PiD), 40 dementia with Lewy bodies TA B L E 1 On the left, the main hallmarks describe cellular health, in cellular aging and in neurodegeneration. On the right, relevant cellular pathways, cellular processes, and pathogenic mechanisms in neurodegeneration.

[7] Nano-structured strategies in combatting neurodegeneration

• Authors: M. Prasanth, Anjali R. Mallya, William C. Cho, Deepa Mundekkad
• Year: 2025
• Venue: Frontiers in Bioengineering and Biotechnology
• URL: https://www.semanticscholar.org/paper/00ba50d2256573e32d29e5739ddd4262e82e7a58
• DOI: 10.3389/fbioe.2025.1638668
• PMID: 41409624
• PMCID: 12705558
• Citations: 1
• Summary: This review explores the potential of the recent nanostructured technologies in managing the complexities of PD and aims to chart a course for future research directions, with special reference to innovative approaches in disease diagnosis.
• Evidence snippets:
• Snippet 1 (score: 0.512) > The complexity of PD is intensified by a combination of genetic, epigenetic, and environmental factors. In this, genetic predisposition plays a significant role, with several genes being intimately linked to the risk of PD eventuality. The fact that such genetic mutations can be inherited through autosomal dominant or recessive inheritance patterns further increase the individual's susceptibility (Ye et al., 2023). Additionally, epigenetic modifications are also known to dominate the progression of PD by regulating genes related to cellular processes like Molecular mechanisms involved in the manifestation of PD. Some of the key processes involved in the interconnected molecular mechanisms underlying PD pathogenesis are α-synuclein aggregation, mitochondrial dysfunction, oxidative stress, impaired protein degradation, and neuroinflammation. Many of these pathways influence one another, amplifying neurodegeneration and contributing to disease progression. autophagy, inflammation, and oxidative stress (Chen et al., 2022). Understanding the crosstalk between genetic and epigenetic changes in gene expression will also help to uncover potential avenues for early diagnosis, targeted therapies, and personalized interventions. Even though multiple genetic factors contribute to neurodegeneration, mutations in seven major genes such as VPS35, DJ-1, GBA1, LRRK2, PINK1, PRKN, and SNCA impact neuronal health the most through distinct pathways. VPS35 is part of the retromer complex involved in endosomal sorting; a mutation in the VPS35 gene, specifically the D620N mutation, can lead to autosomal-dominant PD. This disrupts the normal functioning of the retromer complex impairing endosomal sorting and protein recycling, further leading to abnormal protein accumulation and neurodegeneration (Rowlands and Moore, 2024). Studies in knock-in mouse models reveal that this mutation also amplifies glutamate synapse activity, contributing to excitotoxicity and neuronal damage (Kadgien et al., 2021). DJ-1 functions as an antioxidative stress protein; its loss heightens oxidative damage to neurons.

[8] Tauroursodeoxycholic acid: a potential therapeutic tool in neurodegenerative diseases

• Authors: K. Khalaf, P. Tornese, Antoniangela Cocco, A. Albanese
• Year: 2022
• Venue: Translational Neurodegeneration
• URL: https://www.semanticscholar.org/paper/fc8297123bf79eab6ffaf43a48b65af2cb896378
• DOI: 10.1186/s40035-022-00307-z
• PMID: 35659112
• PMCID: 9166453
• Citations: 114
• Influential citations: 3
• Summary: Preclinical studies indicate that TUDCA exerts its effects not only by regulating and inhibiting the apoptotic cascade, but also by reducing oxidative stress, protecting the mitochondria, producing an anti-neuroinflammatory action, and acting as a chemical chaperone to maintain the stability and correct folding of proteins.
• Evidence snippets:
• Snippet 1 (score: 0.512) > Neurodegenerative diseases are characterized by the progressive deterioration of neuronal function, ultimately leading to a loss of specific neurons. These are incurable diseases, and current available therapies, at best, only manage clinical symptoms. Although the pathological hallmarks and the affected neuronal populations can vary, when considered at the genetic, molecular, or cellular level, relatively few players and patterns crop up repeatedly, such as the aggregation and spread of misfolded proteins, selective vulnerability of particular neurons, and activation of immune responses [1,2]. The possibility that such pathological phenomena arise from common mechanisms that play out across different brain regions and cell types, or simply as the same steps along a shared pathway to neurodegeneration, raises hope for finding treatments that modify the disease course of neurodegenerative diseases. > The peculiar anatomical specificity of neuronal degeneration characterizes the profile of neurodegenerative diseases. An early pathological feature in Alzheimer's disease (AD) is the degeneration of cholinergic neurons in the subcortical nuclei of the basal forebrain; in Parkinson's disease (PD) degeneration of dopaminergic neurons occurs in the substantia nigra pars compacta. Huntington's disease (HD), instead, is characterized by selective neuronal loss in the striatum; in amyotrophic lateral sclerosis (ALS) degeneration prevalently affects corticospinal and spinomuscular motor neurons. The progression of neurodegeneration varies considerably from a few years to several decades in different diseases. ALS is the most fast-progressing neurodegenerative condition, with survival varying from 2 to 4 years from onset [3]. Other neurodegenerative conditions have a slower course, although with significant individual variations in progression trajectories [4]. > Stimuli that trigger the onset of metabolic derangement and lead to neuronal death include reactive oxygen species (ROS) production, misfolded protein accumulation, and endoplasmic reticulum (ER) stress. These stimuli are kept in check by mechanisms protecting the cell, such as the survival pathways [5].

[9] Common immunopathogenesis of central nervous system diseases: the protein-homeostasis-system hypothesis

• Authors: Kyung-Yil Lee
• Year: 2022
• Venue: Cell & Bioscience
• URL: https://www.semanticscholar.org/paper/2984270ae67451b93007040848d9694d19714c9f
• DOI: 10.1186/s13578-022-00920-5
• PMID: 36384812
• PMCID: 9668226
• Citations: 9
• Influential citations: 1
• Summary: This article proposes a common immunopathogenesis of CNS diseases, including prion diseases, Alzheimer’s disease, and genetic diseases, through the PHS hypothesis, which proposes that the immune systems in the host control those substances according to the size and biochemical properties of the substances.
• Evidence snippets:
• Snippet 1 (score: 0.511) > There are hundreds of genetic diseases of the CNS. The defective proteins in genetic disorders include structural proteins for neurotransmitter receptors and other receptors or ion channels on CNS cells, and proteins involved in enzymatic process, metabolism (transport), or signal transduction pathways in various communication systems [98]. Because a discussion of each genetic disease is beyond the scope of this review, only crucial points about the pathogenesis of genetic diseases are discussed. Singlegene defect diseases of the CNS can be caused by a defective product from a gene, i.e., a protein deficiency or a malfunctioning protein. In general, autosomal dominant genetic diseases are caused by structural protein defects, and autosomal recessive diseases are caused by defects in enzymatic proteins. However, certain genetic diseases that involve an enzymatic or multifunctional protein defect can induce structural cell injury during the natural course of the illness. > Patients with genetic diseases, including HD, familial JCD, GSS, and the genetic forms of AD and PD, show different clinical manifestations from other affected people in their family, including the time of onset of neurological symptoms, speed of progression of the disease, and prognosis, suggesting that phenotypes can vary even when the genotypes are identical. Likewise, similar phenotypes of CNS symptoms can be found in different genetic diseases. In genetic animal models, the phenotypes of single gene knockout can vary by strain in mice, and the clinical manifestations of a gene defect can differ between mice and humans, and mice null for some genes have also no observable phenotypic abnormalities compared with controls [99]. These findings suggest that default of a protein might be at least partly controlled by individual's control systems and that there might exist a similar immune/repair system against cell injury in genetic diseases. > The pathophysiology of most genetic diseases in the CNS is complex because any affected gene is associated with numerous proteins and their corresponding activations of genes and epigenetic changes that occur during disease processes. Thus, the use of a genetic marker for diagnosing or predicting a prognosis remains impractical in clinical settings [100].

[10] Does Vitamin C Influence Neurodegenerative Diseases and Psychiatric Disorders?

• Authors: J. Kocot, Dorota Luchowska-Kocot, M. Kiełczykowska, I. Musik, J. Kurzepa
• Year: 2017
• Venue: Nutrients
• URL: https://www.semanticscholar.org/paper/296b393c4fe639ac74f9f8e31e6bdd399f9f638e
• DOI: 10.3390/nu9070659
• PMID: 28654017
• PMCID: 5537779
• Citations: 196
• Influential citations: 3
• Summary: The aim of this review is to update the current state of knowledge of the role of vitamin C on neurodegenerative diseases including Alzheimer’s disease, Parkinson’'s disease, Huntington’ s disease, multiple sclerosis and amyotrophic sclerosis, as well as psychiatric disorders including depression, anxiety and schizophrenia, to understanding of the mechanisms underlying possible therapeutic properties of ascorbic acid in the presented disorders.
• Evidence snippets:
• Snippet 1 (score: 0.497) > Huntington's disease (HD) is a genetic, autosomal dominant disorder characterized by general neurodegeneration in brain with marked deterioration of medium-sized spiny neurons (MSNs) in the striatum [17,113]. HD is caused by a mutation (a CAG expansion) in the huntingtin gene (HTT), which results in an abnormal polyglutamine expansion in the huntingtin (HTT) protein and consequently HTT aggregation [113]. The mutant HTT alters intracellular Ca 2+ homeostasis, induces mitochondrial dysfunction, disrupts intracellular trafficking and impairs gene transcription [114]. > Clinically, HD is characterized by tripartite clinical features, namely progressive motor dysfunction (so-called choreic movements), neuropsychiatric symptoms and a variety of cognitive deficits [115,116]. Neuropathologically, HD is associated with a progressive, selective neuronal dysfunction and degeneration, especially in the both part of striatum (caudate and putamen) [117,118]. > HD is known to be associated with a failure in energy metabolism, impaired mitochondrial ATP production and oxidative damage [113,[119][120][121]. Other mechanisms, such as excitotoxicity, aberrant glutamatergic, dopaminergic and Ca 2+ signaling mechanisms, metabolic damage, immune response, apoptosis as well as autophagy are also suggested to be involved in HD pathology [119,[121][122][123][124]. > Vit C flux from astrocytes to neurons during synaptic activity is regarded to be essential for protecting neurons against oxidative damage and modulation of neuronal metabolism, thus permitting optimal ATP production [119]. Under physiological conditions, Vit C is released from astrocytes to striatal extracellular fluid during increased synaptic activity. The enhancement of Vit C concentration in striatal extracellular fluid results in SVCT2 translocation to the plasma membrane and consequently Vit C uptake by neurons [119]. In neurons, Vit C is able to scavenge reactive oxygen species generated during synaptic activity and neuronal metabolism.

[11] Seeing Neurodegeneration in a New Light Using Genetically Encoded Fluorescent Biosensors and iPSCs

• Authors: David Stellon, Jana Talbot, A. Hewitt, A. King, A. Cook
• Year: 2023
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/cb02ebf9c117052864b4d55e327e9cf48895ecd0
• DOI: 10.3390/ijms24021766
• PMID: 36675282
• PMCID: 9861453
• Citations: 2
• Summary: GEFB technology presents a plethora of unique sensing capabilities that, when coupled with induced pluripotent stem cells (iPSCs), present a powerful tool for exploring disease mechanisms and identifying novel therapeutics.
• Evidence snippets:
• Snippet 1 (score: 0.492) > Neurodegenerative diseases present with heterogeneous clinical and pathological traits, affecting different neuronal subtypes, non-neuronal cell types such as astrocytes, and diverse anatomical regions. For instance, movement is affected in both amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA); whilst motor neurons are primarily affected in each disease, each have their own unique pathological mechanisms and, subsequently, the age of onset, clinical profile, and regions affected differ. The complexity of the nervous system and cell types within it are reflected in the heterogeneity of mechanisms leading to disease, and this has hampered the identification of treatments to slow, reverse, or halt disease progression. Consequently, neurodegenerative diseases impart a growing socioeconomic burden. > Neurodegeneration may affect individuals at every stage of life; for example, the prevalence and incidence of the two of the most common neurodegenerative diseases-Alzheimer's disease (AD) and Parkinson's disease (PD)-are associated with an advanced age, whereas SMA is usually diagnosed at infancy. Chemotherapy-induced peripheral neuropathy (CIPN) is also a prevalent neurological side effect of cancer survivors (affecting 30-40%), and may affect individuals at any age, albeit a recent study reported the mean age to be 60.9 years [1][2][3]. With ageing populations, many nations are expected to see a significant rise in age-associated neurodegenerative diseases, and filling the mechanistic gap between epidemiological evidence and disease will help to prevent this increase [4]. > Research into the complexities of neurodegeneration is challenging due to varied aetiologies, the wide range of age at presentation, and the involvement of different central and peripheral nervous system cell types. Genetics is the key factor causing familial cases of neurodegeneration. For examples, SMA is one of the most frequent autosomal recessive diseases and most common genetic causes of childhood mortality [5], and Huntington's disease (HD) is a autosomal dominant neurodegenerative disease primarily affecting adults [6].

[12] Metabolic and transcriptomic analysis of Huntington’s disease model reveal changes in intracellular glucose levels and related genes

• Authors: Gepoliano Chaves, Rıfat Emrah Özel, N. V. Rao, Hana Hadiprodjo, Yvonne Da Costa et al.
• Year: 2017
• Venue: Heliyon
• URL: https://www.semanticscholar.org/paper/f28a1c495978f9d84234068188239f1b5962c221
• DOI: 10.1016/j.heliyon.2017.e00381
• PMID: 28920088
• PMCID: 5576993
• Citations: 15
• Summary: The transcriptome of mHTT cell populations is investigated alongside intracellular glucose measurements using a functionalized nanopipette and altered transcript levels of certain genes including Sorcs1, Hh-II and Vldlr are identified, suggesting that these can be used as markers for HD progression.
• Evidence snippets:
• Snippet 1 (score: 0.487) > Huntington's Disease (HD) is a progressive, autosomal dominant neurodegenerative disease that produces physical, mental and emotional changes due to loss of critically important brain neurons. The genetic basis for HD is an expansion of cytosine-adenine-guanine (CAG) repeats in the huntingtin (HTT or IT15) gene that leads to the formation of a prolonged polyglutamine (polyQ) tract in the N-terminal region of the mutant huntingtin protein (mHTT). The wild type huntingtin protein (HTT) is important for the intracellular transport and trafficking of proteins, organelles and vesicles. The expansion of glutamine (>36 repeats) produces a gain of function mHTT that affects the healthy function of cellular machinery, ultimately resulting in neurotoxicity and detrimental cell lethality in the brain [1]. > Considerable research efforts have been made to elucidate the molecular and cellular mechanisms underlying HD pathology. The proposed mechanisms through which mHTT causes neurodegeneration include mutant protein aggregation, vesicle association, elevated oxidative stress, excitotoxicity, mitochondrial and transcriptional dysregulation [2,3]. Evidence for several of these mechanisms has been found in post-symptomatic disease models or post-mortem brain samples. Controversially, during the pre-symptomatic stage of HD, cellular architecture and morphology have been found to be disrupted but neurodegeneration has been found to be minimal or absent [4,5]. These studies have been limited to immunohistochemistry, fluorescence staining and immunoblot analysis, and provided static information of HD [6,7]. However, little is known at the early stages of the disease about the dynamics of metabolic and transcriptomic changes, which could be instrumental not only for HD therapy for diagnosed patients but also for at-risk individuals. Striatum, a subcortical part of the forebrain, is the most vulnerable part of the brain in HD, almost disappearing during the course of disease. One of the major clinical symptoms of HD is the loss of the medium spiny neurons in the striatum [8].

[13] Neurodegenerative Disorders: Spotlight on Sphingolipids

• Authors: Frida Mandik, Melissa Vos
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/9e29f2d97ed1915e39b1e55a4c5c9ac14d3e2ea9
• DOI: 10.3390/ijms222111998
• PMID: 34769423
• PMCID: 8584905
• Citations: 24
• Summary: Key findings that demonstrate the relevance of sphingolipids in neurodegenerative diseases are covered and will focus on Neurodegeneration with brain iron accumulation and Parkinson’s disease.
• Evidence snippets:
• Snippet 1 (score: 0.487) > PD is the second most common ND after AD that results in motor symptoms, bradykinesia and rigidity as a consequence of the loss of dopaminergic neurons. PD is characterized by the presence of Lewy bodies, the primary protein structure of which is composed of alpha-synuclein protein aggregates [3]. > Like many NDs, PD is a mostly sporadic disease; however, genes have been identified to be causative when mutated, including SNCA, VPS35, and LRRK2, resulting in autosomal dominant forms of PD, and Parkin and PINK1 to be the most common genes mutated in autosomal recessive forms of PD [3,65]. Despite the identification of these genes, there is no complete understanding of the etiology of PD, which explains the limited efficacy of therapeutics. However, similar mechanisms are present in both sporadic and genetic forms of the disease. Studies on drug abusers with parkinsonism have hinted towards defects at the level of the mitochondrial electron transport chain, which was later confirmed in patients and animal models [66][67][68][69][70]. Furthermore, PINK1-dependent phosphorylation is required for an efficient ETC, and the stimulation of the ETC can alleviate signs in pink1-and drug-related PD animal models [71][72][73]. Additionally, PINK1 exerts a (parallel) function together with Parkin that was first identified in Drosophila [74,75]. These findings were later confirmed in a cellular model in which PINK1-Parkin-mediated mitophagy was identified [76][77][78]. Interestingly, mitochondrial symptoms have been observed in other genetic PD models, including alpha-synuclein-dependent models [79], suggesting that mitochondrial dysfunction plays an important role in the pathogenesis of PD; however, the underlying mechanisms of how mitochondrial dysfunction results in neurodegeneration remains enigmatic. A more recently identified pathway that is linked to PD is the endolysosomal pathway, in which the autosomal dominant PD-related genes play a major role [70].

[14] Molecular mediators, environmental modulators and experience-dependent synaptic dysfunction in Huntington's disease.

• Authors: A. Hannan
• Year: 2004
• Venue: Acta biochimica Polonica
• URL: https://www.semanticscholar.org/paper/8aa0227da705c5450e2868feff8da06605a1973f
• DOI: 10.18388/ABP.2004_3581
• PMID: 15218539
• Citations: 21
• Influential citations: 2
• Summary: Possible molecular and cellular mechanisms mediating the polyglutamine-induced toxic 'gain of function' and associated gene-environment interactions in Huntington's disease are outlined.
• Evidence snippets:
• Snippet 1 (score: 0.481) > Huntington's disease (HD) is an autosomal dominant disorder in which there is progressive neurodegeneration producing motor, cognitive and psychiatric symptoms. HD is caused by a trinucleotide (CAG) repeat mutation, encoding an expanded polyglutamine tract in the huntingtin protein. At least eight other neurodegenerative diseases are caused by CAG/glutamine repeat expansions in different genes. Recent evidence suggests that environmental factors can modify the onset and progression of Huntington's disease and possibly other neurodegenerative disorders. This review outlines possible molecular and cellular mechanisms mediating the polyglutamine-induced toxic 'gain of function' and associated gene-environment interactions in HD. Key aspects of pathogenesis shared with other neurodegenerative diseases may include abnormal protein-protein interactions, selective disruption of gene expression and 'pathological plasticity' of synapses in specific brain regions. Recent discoveries regarding molecular mechanisms of pathogenesis are guiding the development of new therapeutic approaches. Knowledge of gene-environment interactions, for example, could lead to development of 'enviromimetics' which mimic the beneficial effects of specific environmental stimuli. The effects of environmental enrichment on brain and behaviour will also be discussed, together with the general implications for neuroscience research involving animal models.

[15] Dysregulation of Gene Expression in Primary Neuron Models of Huntington's Disease Shows That Polyglutamine-Related Effects on the Striatal Transcriptome May Not Be Dependent on Brain Circuitry

• Authors: H. Runne, E. Régulier, A. Kuhn, D. Zala, O. Gokce et al.
• Year: 2008
• Venue: The Journal of Neuroscience
• URL: https://www.semanticscholar.org/paper/2fdab97748a286332a0055dafc54e64cac231f61
• DOI: 10.1523/JNEUROSCI.3044-08.2008
• PMID: 18815258
• Citations: 100
• Influential citations: 2
• Summary: In vitro models of Huntington's disease comprised of primary striatal neurons expressing N-terminal fragments of mutant Huntingtin faithfully reproduce the gene expression changes seen in human HD, demonstrating that HD-induced dysregulation of the striatal transcriptome might be attributed to intrinsic effects of mutant huntingtin.
• Evidence snippets:
• Snippet 1 (score: 0.478) > ly similar to human HD . Moreover, BDNF is neuroprotective in chemical and genetic models of HD, including the very model we study in these experiments. Although the sum of the data implicating BDNF is very impressive, it is nonetheless likely that extracortical mechanisms also govern striatal neurodegeneration in HD. > Recent studies using regionally restrictive promoters to drive mutant huntingtin expression have suggested that pathological cell-cell interactions contribute to cortical pathogenesis in an HD mouse model (Gu et al., 2005) and also to a major interdependence of cortical and striatal cells in HD pathogenesis (Gu et al., 2007). Moreover, previous studies by our group also show that HD-like pathology and typical motor deficits can be seen in the striata of primates expressing mutant huntingtin in the striatum only (Palfi et al., 2007). Therefore, it is also quite plausible that the range of effects of mutant huntingtin comprises cellularly independent, parallel, and combinatorial toxicities that may all be involved in the pathogenesis of HD. In fact, one could postulate that the strong reproducibility of striatal degeneration despite a wide range of clinical HD phenotypes arises from functionally overlapping pathways that ensure the nearly universal demise of this cell population. > The present findings focus on the transcriptomic level changes in polyQ-affected cells. Although there is considerable evidence to suggest that these changes are primary targets of mutant huntingtin through its direct interactions with transcription and chromatin remodeling factors, it is possible that some of these changes are secondary events, or possibly even reflect nonpathogenic compensatory changes. We cannot discriminate between these possibilities at the present time, but nonetheless, we believe that these transcriptomic indicators can serve as robust readouts for the specific molecular and cellular mechanisms that regulate polyQ-dependent effects and responses. This perspective is wellsupported in animal model data, which show that gene expression changes generally correlate well with behavioral measures in animals with early-tomoderate disease signs and that the RNA changes worsen with disease progression (Luthi-Carter et al., 2002;Hodges et al., 2007;Kuhn et al

[16] Equilibrative nucleoside transporter 3 supports microglial functions and protects against the progression of Huntington's disease in the mouse model.

• Authors: Ying-Sui Lu, Wei-Chien Hung, Yu‐Ting Hsieh, Pei-Yuan Tsai, Tsai-Hsien Tsai et al.
• Year: 2024
• Venue: Brain, behavior, and immunity
• URL: https://www.semanticscholar.org/paper/24f1acd02b8bffd5e4f7cb0604d1d2c4000640a0
• DOI: 10.1016/j.bbi.2024.06.021
• PMID: 38925413
• Citations: 2
• Summary: It is suggested that the delicate balance between microglial metabolism and function is crucial for maintaining brain homeostasis and that ENT3 has a protective role in ameliorating neurodegenerative processes.
• Evidence snippets:
• Snippet 1 (score: 0.477) > Huntington's disease (HD) is a progressive neurodegenerative disorder that primarily affects the central nervous system (CNS). As an inherited autosomal disease, this debilitating condition is characterized by a range of involuntary movements, cognitive deficits, and psychiatric symptoms. HD is caused by the monogenic disorder of expanded CAG repeats in the huntingtin (Htt) gene (Tabrizi et al., 2020), leading to the accumulation of mutant huntingtin (mHTT). The mHTT protein undergoes abnormal folding, leading to the formation of protein aggregates within the cells. These aggregates interfere with essential cellular processes, impairing neuronal function and survival, and are positively correlated with massive neuronal cell death and degeneration. The striatum, a brain region involved in motor control, is affected particularly severely in HD. Currently, there is no cure for HD, with only limited treatment strategies available to manage the symptoms and slow down disease progression. > Although HD has a well-defined genetic origin, the molecular and cellular mechanisms underlying the pathogenesis of HD are complex. While aggregate formation and toxic fragment production lead to cellular transcriptional deregulation, altered protein homeostasis, and mitochondrial dysfunction, neuroglial disturbance, such as neuroinflammation and impaired glutamate uptake by astrocytes, is another crucial contributor to HD pathophysiology (Jimenez-Sanchez et al., 2017). Interestingly, the neuroinflammation and the protein-degradation-resultant defects such as autophagiclysosomal dysfunction in HD are shared features with other neurological diseases such as Alzheimer's disease (AD) or lysosomal storage diseases (LSDs). The majority of LSDs present different degrees of pathology in the CNS and neurodegeneration in multiple brain regions. Depending on the specific type of metabolite accumulation, the patients vary in affected age or neuronal subtypes (Platt et al., 2012). The commonality between these diseases suggests a potential shared molecular mechanism caused by abnormal protein aggregation, autophagic-lysosomal dysfunction, and neuroinflammation.

[17] Neuroprotective Effects of Synaptic Modulation in Huntington's Disease R6/2 Mice

• Authors: E. Stack, A. Dedeoglu, Karen M. Smith, K. Cormier, James K. Kubilus et al.
• Year: 2007
• Venue: The Journal of Neuroscience
• URL: https://www.semanticscholar.org/paper/7af953df6d61b29f7fdc00e8f7f21ed568bbecca
• DOI: 10.1523/JNEUROSCI.4318-07.2007
• PMID: 18032664
• Citations: 82
• Summary: Results suggest that synaptic stress is likely to contribute to neurodegeneration in HD, whereas transsynaptic trophic influences may not be as salient.
• Evidence snippets:
• Snippet 1 (score: 0.477) > Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder in which the neostriatum degenerates early and most severely, with involvement of other brain regions. There is significant evidence that excitotoxicity may play a role in striatal degeneration through altered afferent corticostriatal and nigrostriatal projections that may modulate synaptically released striatal glutamate. Glutamate is a central tenant in provoking excitotoxic cell death in striatal neurons already weakened by the collective molecular events occurring in HD. In addition, transcriptional suppression of trophic factors occurs in human and transgenic mouse models of HD, suggesting that a loss of trophic support might contribute to degeneration. Since anti-glutamate approaches have been effective in improving disease phenotype in HD mice, we examined whether deafferentation of the corticostriatal and nigrostriatal pathways may mitigate striatal stress and neurodegeneration. Both surgical and chemical lesions of the corticostriatal and nigrostriatal pathways, respectively, improved the behavioral, neuropathological, and biochemical phenotype in R6/2 transgenic mice and extended survival. Decortication ameliorated hindlimb clasping, striatal neuron atrophy, and huntingtin-positive aggregates, improved N-acetyl aspartate/creatine levels, reduced oxidative stress, and significantly lowered striatal glutamate levels. In addition, 6-hydroxydopamine lesioned mice showed extended survival along with a significant reduction in striatal glutamate. These results suggest that synaptic stress is likely to contribute to neurodegeneration in HD, whereas transsynaptic trophic influences may not be as salient. Thus, modulation of synaptic influences continues to have therapeutic potential in HD.

[18] Protein network analysis links the NSL complex to Parkinson's disease via mitochondrial and nuclear biology.

• Authors: K. Kelly, P. Lewis, H. Plun-Favreau, C. Manzoni
• Year: 2023
• Venue: Molecular omics
• URL: https://www.semanticscholar.org/paper/b857cc817831d2a3869de58ddc869d7312f016a0
• DOI: 10.1039/d2mo00325b
• PMID: 37427757
• Summary: The mitochondrial NSL interactome is found to be significantly enriched for the protein products of PD-associated genes, including the Mendelian PD genes LRRK2 and VPS35, and nuclear processes to be amongst those most significantly enriched within the PD- associated N SL interactome.
• Evidence snippets:
• Snippet 1 (score: 0.475) > Parkinson's disease (PD) is the most common movement disorder of old age (465 years). 1 Furthermore, global prevalence predictions suggest that the number of affected individuals more than doubled in 25 years, with an estimated 6.1 million people living with PD in 2016. 2 The movement aspects of PD are triggered by the progressive degeneration of neurons within the Substantia Nigra pars compacta (SNpc). The consequent depletion of dopamine (DA) within nigro-striatal circuits gives origin to the debilitating triad of PD clinical symptoms: rigidity, asymmetric resting tremor, and bradykinesia. Pathologically, neuronal loss is paired with the deposition of a-synuclein aggregates in intracellular inclusions called Lewy bodies. 3 The progression of PD is complex, with involvement of additional brain areas whose degeneration is responsible for the clinical manifestation of additional non-motor symptoms. 4 PD has a heterogenous presentation and the interindividual differences in disease onset and progression, typical of complex disorders, hint at the existence of a personal burden of risk, a mix of genetic susceptibility factors and environmental exposures which differ on a case-to-case basis. 4 Potentiation of DA signalling is the only available therapeutic intervention, achieved via DA replacement and/or by inhibition of DA catabolism and re-uptake at the synapse. However, this is a symptomatic intervention that does not halt neurodegeneration. 5 As such, precise delineation of the molecular mechanisms of PD neurodegeneration is critical, to implicate novel research avenues for the development of disease-modifying treatments. > A minority of PD cases are familial (fPD), caused by highly penetrant mutations that segregate with the disease. The study of monogenic forms of PD has facilitated the elucidation of common cellular phenotypes, and the molecular patterns underpinning them.

[19] Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

• Authors: M. M. Wong, L. Watson, Esther B. E. Becker
• Year: 2017
• Venue: Journal of neurology & neuromedicine
• URL: https://www.semanticscholar.org/paper/0d962652305116e383ab260b9e82d3a5ffe1722f
• DOI: 10.29245/2572.942X/2017/7.1134
• PMID: 28825058
• PMCID: 5558869
• Citations: 10
• Summary: This review focuses on recent breakthroughs in generating human iPSC-derived Purkinje cells and highlights the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.
• Evidence snippets:
• Snippet 1 (score: 0.473) > dominant polyglutamine spinocerebellar ataxias (SCAs) are the most studied forms of ataxias. Despite significant clinical and genetic heterogeneity, emerging evidence points to the existence of common pathogenic mechanisms that may be shared by several genetically distinct forms of cerebellar ataxias (reviewed in5-8). However, it is still unclear how the proposed pathological pathways ultimately result in cerebellar dysfunction and degeneration, predominantly affecting Purkinje cells. > Understanding disease mechanisms is key to treating neurodegenerative disorders. The heterogeneous nature of the cerebellar ataxias combined with the unavailability of human brain tissue and the lack of reliable disease models have, however, hampered our understanding of the molecular disease mechanisms underlying cerebellar ataxias and thus, the development of effective therapies. Although mouse models of several cerebellar ataxias, including FRDA and SCAs, have provided valuable insights into the pathophysiology of these disorders (reviewed in9), many questions remain about the observed species differences in disease phenotypes and the effectiveness of potential drugs in clinical trials. > To help translate research from animal models into novel treatments for ataxia patients, it is essential to validate findings in the relevant affected human cell types, particularly in cerebellar Purkinje cells. The current obstacles might be overcome by exploiting recently developed human induced pluripotent stem cell (iPSC) technology and neuronal differentiation protocols.

[20] Manifestation of Huntington’s disease pathology in human induced pluripotent stem cell-derived neurons

• Authors: E. Nekrasov, V. Vigont, S. Klyushnikov, O. Lebedeva, E. Vassina et al.
• Year: 2016
• Venue: Molecular Neurodegeneration
• URL: https://www.semanticscholar.org/paper/13d321875e6cb13ab9cd5f03864bc3796baee6cc
• DOI: 10.1186/s13024-016-0092-5
• PMID: 27080129
• PMCID: 4832474
• Citations: 145
• Influential citations: 4
• Summary: This data is the first to demonstrate the direct link of nuclear morphology and SOC calcium deregulation to mutant huntingtin protein expression in iPSCs-derived neurons with disease-mimetic hallmarks, providing a valuable tool for identification of candidate anti-HD drugs.
• Evidence snippets:
• Snippet 1 (score: 0.471) > Huntington's disease (HD) is an incurable autosomal dominant hereditary neurodegenerative disorder that typically manifests between 35-55 years of age. The worldwide prevalence of HD ranges from 0.5 (Japan) to 5-7 (Europe, USA, and Canada) cases per 100,000 individuals. HD is characterized by extensive neurodegeneration, primarily affecting GABAergic medium spiny (GABA MS) neurons in the striatum. Other brain regions also show substantial neuronal damage with disease progression [1]. > HD is caused by an expansion of cytosine-adenineguanine (CAG) repeats in the huntingtin gene (HTT) that leads to a pathological elongation of polyglutamine repeats in the huntingtin protein (HTT). The HD phenotype develops when the number of trinucleotide repeats in the HTT gene exceeds 36. The HTT protein normally interacts with hundreds of other proteins, and probably has multiple biological functions [2]. While wild-type HTT (wtHTT) and mutant HTT (mHTT) proteins are ubiquitously expressed in the brain, neurodegeneration in HD mainly affects the striatum. Furthermore, the neurotoxic actions of mHTT are significantly higher in the striatal neurons of aged vs. young animals [3]. Recent magnetic resonance imaging and positron emission tomography studies demonstrated that striatal atrophy in human HD patients is detectable even at 10 years before the onset of disease symptoms [4]. Nevertheless, the mechanism of mHTT action is not fully understood, and is often considered multifactorial. > HD pathology is linked to the deregulation of multiple cellular processes (e.g., autophagy [5], calcium homeostasis [6], and assorted mitochondrial functions [7,8]), but the critical factors behind HD advance are still unknown. Various challenges complicate the deciphering of HD molecular mechanisms, including a limited access to human neurons, the complexity of the molecular mechanisms underlying HD pathology, and the lack of adequate animal models.

Notes

• This provider combines search_papers_by_relevance with snippet_search.
• No synthesis or second-stage model call is performed.