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Cold Spring Harbor Perspectives in... Mar 2018α-Synuclein is an abundant neuronal protein that is highly enriched in presynaptic nerve terminals. Genetics and neuropathology studies link α-synuclein to Parkinson's... (Review)
Review
α-Synuclein is an abundant neuronal protein that is highly enriched in presynaptic nerve terminals. Genetics and neuropathology studies link α-synuclein to Parkinson's disease (PD) and other neurodegenerative disorders. Accumulation of misfolded oligomers and larger aggregates of α-synuclein defines multiple neurodegenerative diseases called synucleinopathies, but the mechanisms by which α-synuclein acts in neurodegeneration are unknown. Moreover, the normal cellular function of α-synuclein remains debated. In this perspective, we review the structural characteristics of α-synuclein, its developmental expression pattern, its cellular and subcellular localization, and its function in neurons. We also discuss recent progress on secretion of α-synuclein, which may contribute to its interneuronal spread in a prion-like fashion, and describe the neurotoxic effects of α-synuclein that are thought to be responsible for its role in neurodegeneration.
Topics: Animals; Humans; Mice; Mice, Transgenic; Neurons; Parkinson Disease; Synapses; alpha-Synuclein
PubMed: 28108534
DOI: 10.1101/cshperspect.a024091 -
Neurobiology of Disease Jan 2023Synucleinopathies, including Parkinson's disease (PD), dementia with Lewy Bodies (DLB), and multiple system atrophy (MSA), are characterized by the misfolding and... (Review)
Review
Synucleinopathies, including Parkinson's disease (PD), dementia with Lewy Bodies (DLB), and multiple system atrophy (MSA), are characterized by the misfolding and subsequent aggregation of alpha-synuclein (α-syn) that accumulates in cytoplasmic inclusions bodies in the cells of affected brain regions. Since the seminal report of likely-aggregated α-syn presence within the Lewy bodies by Spillantini et al. in 1997, the keyword "synuclein aggregation" has appeared in over 6000 papers (Source: PubMed October 2022). Studying, observing, describing, and quantifying α-syn aggregation is therefore of paramount importance, whether it happens in tubo, in vitro, in post-mortem samples, or in vivo. The past few years have witnessed tremendous progress in understanding aggregation mechanisms and identifying various polymorphs. In this context of growing complexity, it is of utmost importance to understand what tools we possess, what exact information they provide, and in what context they may be applied. Nonetheless, it is also crucial to rationalize the relevance of the information and the limitations of these methods for gauging the final result. In this review, we present the main techniques that have shaped the current views about α-syn structure and dynamics, with particular emphasis on the recent breakthroughs that may change our understanding of synucleinopathies.
Topics: Humans; alpha-Synuclein; Synucleinopathies; Parkinson Disease; Multiple System Atrophy; Lewy Bodies
PubMed: 36527982
DOI: 10.1016/j.nbd.2022.105966 -
Neuron May 2023Pathogenic α-synuclein and tau are critical drivers of neurodegeneration, and their mutations cause neuronal loss in patients. Whether the underlying preferential...
Pathogenic α-synuclein and tau are critical drivers of neurodegeneration, and their mutations cause neuronal loss in patients. Whether the underlying preferential neuronal vulnerability is a cell-type-intrinsic property or a consequence of increased expression levels remains elusive. Here, we explore cell-type-specific α-synuclein and tau expression in human brain datasets and use deep phenotyping as well as brain-wide single-cell RNA sequencing of >200 live neuron types in fruit flies to determine which cellular environments react most to α-synuclein or tau toxicity. We detect phenotypic and transcriptomic evidence of differential neuronal vulnerability independent of α-synuclein or tau expression levels. Comparing vulnerable with resilient neurons in Drosophila enabled us to predict numerous human neuron subtypes with increased intrinsic susceptibility to pathogenic α-synuclein or tau. By uncovering synapse- and Ca homeostasis-related genes as tau toxicity modifiers, our work paves the way to leverage neuronal identity to uncover modifiers of neurodegeneration-associated toxic proteins.
Topics: Humans; alpha-Synuclein; tau Proteins; Brain; Neurons; Head
PubMed: 36948206
DOI: 10.1016/j.neuron.2023.02.033 -
Brain Pathology (Zurich, Switzerland) May 2016Parkinson's disease (PD) is a common neurodegenerative disorder, characterized pathologically by the presence of α-synuclein (α-syn)-rich Lewy bodies. As clinical... (Review)
Review
Parkinson's disease (PD) is a common neurodegenerative disorder, characterized pathologically by the presence of α-synuclein (α-syn)-rich Lewy bodies. As clinical diagnosis of PD is challenging, misdiagnosis is common, highlighting the need for disease-specific and early stage biomarkers. Both early diagnosis of PD and adequate tracking of disease progression could significantly improve outcomes for patients, particularly in regard to existing and future disease modifying treatments. Given its critical roles in PD pathogenesis, α-syn may be useful as a biomarker of PD. The aim of this review is, therefore, to summarize the efficacy of tissue and body fluid α-syn measurements in the detection of PD as well as monitoring disease progression. In comparison to solid tissue specimens and biopsies, biofluid α-syn levels may be the most promising candidates in PD diagnosis and progression based on specificity, sensitivity and availability. Although α-syn has been tested most extensively in cerebrospinal fluid (CSF), the relatively invasive procedure for collecting CSF is not suitable in most clinical settings, leading to investigation of plasma, blood and saliva as alternatives. The exploration of combined biomarkers, along with α-syn, to improve diagnostic accuracy is also likely required.
Topics: Biomarkers; Humans; Parkinson Disease; alpha-Synuclein
PubMed: 26940058
DOI: 10.1111/bpa.12370 -
Cell Jun 2022Alpha-synuclein (αS) is a conformationally plastic protein that reversibly binds to cellular membranes. It aggregates and is genetically linked to Parkinson's disease...
Alpha-synuclein (αS) is a conformationally plastic protein that reversibly binds to cellular membranes. It aggregates and is genetically linked to Parkinson's disease (PD). Here, we show that αS directly modulates processing bodies (P-bodies), membraneless organelles that function in mRNA turnover and storage. The N terminus of αS, but not other synucleins, dictates mutually exclusive binding either to cellular membranes or to P-bodies in the cytosol. αS associates with multiple decapping proteins in close proximity on the Edc4 scaffold. As αS pathologically accumulates, aberrant interaction with Edc4 occurs at the expense of physiologic decapping-module interactions. mRNA decay kinetics within PD-relevant pathways are correspondingly disrupted in PD patient neurons and brain. Genetic modulation of P-body components alters αS toxicity, and human genetic analysis lends support to the disease-relevance of these interactions. Beyond revealing an unexpected aspect of αS function and pathology, our data highlight the versatility of conformationally plastic proteins with high intrinsic disorder.
Topics: Humans; Parkinson Disease; Processing Bodies; RNA Stability; alpha-Synuclein
PubMed: 35688132
DOI: 10.1016/j.cell.2022.05.008 -
Nature Feb 2020Synucleinopathies are neurodegenerative diseases that are associated with the misfolding and aggregation of α-synuclein, including Parkinson's disease, dementia with...
Synucleinopathies are neurodegenerative diseases that are associated with the misfolding and aggregation of α-synuclein, including Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Clinically, it is challenging to differentiate Parkinson's disease and multiple system atrophy, especially at the early stages of disease. Aggregates of α-synuclein in distinct synucleinopathies have been proposed to represent different conformational strains of α-synuclein that can self-propagate and spread from cell to cell. Protein misfolding cyclic amplification (PMCA) is a technique that has previously been used to detect α-synuclein aggregates in samples of cerebrospinal fluid with high sensitivity and specificity. Here we show that the α-synuclein-PMCA assay can discriminate between samples of cerebrospinal fluid from patients diagnosed with Parkinson's disease and samples from patients with multiple system atrophy, with an overall sensitivity of 95.4%. We used a combination of biochemical, biophysical and biological methods to analyse the product of α-synuclein-PMCA, and found that the characteristics of the α-synuclein aggregates in the cerebrospinal fluid could be used to readily distinguish between Parkinson's disease and multiple system atrophy. We also found that the properties of aggregates that were amplified from the cerebrospinal fluid were similar to those of aggregates that were amplified from the brain. These findings suggest that α-synuclein aggregates that are associated with Parkinson's disease and multiple system atrophy correspond to different conformational strains of α-synuclein, which can be amplified and detected by α-synuclein-PMCA. Our results may help to improve our understanding of the mechanism of α-synuclein misfolding and the structures of the aggregates that are implicated in different synucleinopathies, and may also enable the development of a biochemical assay to discriminate between Parkinson's disease and multiple system atrophy.
Topics: Amyloid; Brain Chemistry; Circular Dichroism; Endopeptidase K; Humans; Multiple System Atrophy; Parkinson Disease; Protein Conformation; Protein Denaturation; Protein Folding; Spectroscopy, Fourier Transform Infrared; alpha-Synuclein
PubMed: 32025029
DOI: 10.1038/s41586-020-1984-7 -
The Lancet. Neurology Aug 2015Progressive neuronal cell loss in a small subset of brainstem and mesencephalic nuclei and widespread aggregation of the α-synuclein protein in the form of Lewy bodies... (Review)
Review
Progressive neuronal cell loss in a small subset of brainstem and mesencephalic nuclei and widespread aggregation of the α-synuclein protein in the form of Lewy bodies and Lewy neurites are neuropathological hallmarks of Parkinson's disease. Most cases occur sporadically, but mutations in several genes, including SNCA, which encodes α-synuclein, are associated with disease development. The discovery and development of therapeutic strategies to block cell death in Parkinson's disease has been limited by a lack of understanding of the mechanisms driving neurodegeneration. However, increasing evidence of multiple pivotal roles of α-synuclein in the pathogenesis of Parkinson's disease has led researchers to consider the therapeutic potential of several strategies aimed at reduction of α-synuclein toxicity. We critically assess the potential of experimental therapies targeting α-synuclein, and discuss steps that need to be taken for target validation and drug development.
Topics: Animals; Drug Discovery; Humans; Parkinson Disease; alpha-Synuclein
PubMed: 26050140
DOI: 10.1016/S1474-4422(15)00006-X -
Brain : a Journal of Neurology Sep 2023The critical role of alpha-synuclein in Parkinson's disease represents a pivotal discovery. Some progress has been made over recent years in identifying... (Review)
Review
The critical role of alpha-synuclein in Parkinson's disease represents a pivotal discovery. Some progress has been made over recent years in identifying disease-modifying therapies for Parkinson's disease that target alpha-synuclein. However, these treatments have not yet shown clear efficacy in slowing the progression of this disease. Several explanations exist for this issue. The pathogenesis of Parkinson's disease is complex and not yet fully clarified and the heterogeneity of the disease, with diverse genetic susceptibility and risk factors and different clinical courses, adds further complexity. Thus, a deep understanding of alpha-synuclein physiological and pathophysiological functions is crucial. In this review, we first describe the cellular and animal models developed over recent years to study the physiological and pathological roles of this protein, including transgenic techniques, use of viral vectors and intracerebral injections of alpha-synuclein fibrils. We then provide evidence that these tools are crucial for modelling Parkinson's disease pathogenesis, causing protein misfolding and aggregation, synaptic dysfunction, brain plasticity impairment and cell-to-cell spreading of alpha-synuclein species. In particular, we focus on the possibility of dissecting the pre- and postsynaptic effects of alpha-synuclein in both physiological and pathological conditions. Finally, we show how vulnerability of specific neuronal cell types may facilitate systemic dysfunctions leading to multiple network alterations. These functional alterations underlie diverse motor and non-motor manifestations of Parkinson's disease that occur before overt neurodegeneration. However, we now understand that therapeutic targeting of alpha-synuclein in Parkinson's disease patients requires caution, since this protein exerts important physiological synaptic functions. Moreover, the interactions of alpha-synuclein with other molecules may induce synergistic detrimental effects. Thus, targeting only alpha-synuclein might not be enough. Combined therapies should be considered in the future.
Topics: Animals; alpha-Synuclein; Animals, Genetically Modified; Disease Models, Animal; Neurons; Parkinson Disease; Humans
PubMed: 37183455
DOI: 10.1093/brain/awad150 -
Science (New York, N.Y.) Dec 2017Oligomeric species populated during the aggregation process of α-synuclein have been linked to neuronal impairment in Parkinson's disease and related neurodegenerative...
Oligomeric species populated during the aggregation process of α-synuclein have been linked to neuronal impairment in Parkinson's disease and related neurodegenerative disorders. By using solution and solid-state nuclear magnetic resonance techniques in conjunction with other structural methods, we identified the fundamental characteristics that enable toxic α-synuclein oligomers to perturb biological membranes and disrupt cellular function; these include a highly lipophilic element that promotes strong membrane interactions and a structured region that inserts into lipid bilayers and disrupts their integrity. In support of these conclusions, mutations that target the region that promotes strong membrane interactions by α-synuclein oligomers suppressed their toxicity in neuroblastoma cells and primary cortical neurons.
Topics: Cell Line, Tumor; Cell Membrane; Cerebral Cortex; Humans; Lipid Bilayers; Mutation; Neurons; Nuclear Magnetic Resonance, Biomolecular; Parkinson Disease; Protein Aggregation, Pathological; alpha-Synuclein
PubMed: 29242346
DOI: 10.1126/science.aan6160 -
Journal of Parkinson's Disease 2019The gastrointestinal (GI) tract is equipped with robust immune defenses which protect the organism from infection. Enteric nerves are front and center in this defensive... (Review)
Review
The gastrointestinal (GI) tract is equipped with robust immune defenses which protect the organism from infection. Enteric nerves are front and center in this defensive network, even in the most primitive organisms. Neuropeptides exhibit potent antimicrobial activity in the vicinity of the nerve and attract the innate and adaptive immune systems to help confine the invading agent. Alpha-synuclein (αS) has many biophysical characteristics of antimicrobial peptides and binds small vesicles such as those carrying endocytosed viruses. It is induced in nerve cells in response to viral and bacterial infections. It renders the nerve cell resistant to viral infection and propagation. It signals the immune system by attracting neutrophils and macrophages, and by activating dendritic cells. Most remarkably αS is trafficked to the central nervous system (CNS) conferring immunity in advance of an infection. Chronic GI infection or breakdown of the epithelial barrier can cause αS to accumulate and form neurotoxic aggregates. Overproduction of αS in the enteric nervous system (ENS) and its chronic trafficking to the CNS may damage nerves and lead to Parkinson's disease. Targeting the formation of αS aggregates in the ENS may therefore slow the progression of the disease.
Topics: Animals; Antimicrobial Cationic Peptides; Enteric Nervous System; Humans; Immunity; Neuropeptides; Parkinson Disease; alpha-Synuclein
PubMed: 31594249
DOI: 10.3233/JPD-191702