-
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 -
Nature Reviews. Neuroscience Jan 2013Disorders characterized by α-synuclein (α-syn) accumulation, Lewy body formation and parkinsonism (and in some cases dementia) are collectively known as Lewy body... (Review)
Review
Disorders characterized by α-synuclein (α-syn) accumulation, Lewy body formation and parkinsonism (and in some cases dementia) are collectively known as Lewy body diseases. The molecular mechanism (or mechanisms) through which α-syn abnormally accumulates and contributes to neurodegeneration in these disorders remains unknown. Here, we provide an overview of current knowledge and prevailing hypotheses regarding the conformational, oligomerization and aggregation states of α-syn and their role in regulating α-syn function in health and disease. Understanding the nature of the various α-syn structures, how they are formed and their relative contributions to α-syn-mediated toxicity may inform future studies aiming to develop therapeutic prevention and intervention.
Topics: Animals; Humans; Models, Biological; Neurodegenerative Diseases; Protein Conformation; alpha-Synuclein
PubMed: 23254192
DOI: 10.1038/nrn3406 -
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 -
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 -
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 -
Handbook of Clinical Neurology 2022Alpha-synuclein (α-synuclein) is a small, acidic protein containing 140 amino acids, highly expressed in the brain and primarily localized in the presynaptic terminals.... (Review)
Review
Alpha-synuclein (α-synuclein) is a small, acidic protein containing 140 amino acids, highly expressed in the brain and primarily localized in the presynaptic terminals. It is found in high concentrations in Lewy Bodies, proteinaceous aggregates that constitute a typical histopathologic hallmark of Parkinson's disease. Altered environmental conditions, genetic mutations and post-translational changes can trigger abnormal aggregation processes with the increased frequency of oligomers, protofibrils, and fibrils formation that perturbs the neuronal homeostasis leading to cell death. Relevant to neuronal activity, a function of α-synuclein that has been extensively detailed is its regulatory actions in the trafficking of synaptic vesicles, including the processes of exocytosis, endocytosis and neurotransmitter release. Most recently, increasing attention has been paid to the possible role that α-synuclein plays at a postsynaptic level by interacting with selective subunits of the glutamate N-methyl-d-aspartate receptor, altering the corticostriatal plasticity of distinct neuronal populations.
Topics: Animals; Corpus Striatum; Disease Models, Animal; Humans; Lewy Bodies; Models, Animal; Parkinson Disease; alpha-Synuclein
PubMed: 35034731
DOI: 10.1016/B978-0-12-819410-2.00008-4 -
International Journal of Biological... Jul 2017Parkinson's disease (PD) is a neurological disorder marked by the presence of cytoplasmic inclusions, Lewy bodies (LBs) and Lewy neurites (LNs) as well as the... (Review)
Review
Parkinson's disease (PD) is a neurological disorder marked by the presence of cytoplasmic inclusions, Lewy bodies (LBs) and Lewy neurites (LNs) as well as the degeneration of dopamine producing neurons in the substantia nigra region of the brain. The LBs and LNs in PD are mainly composed of aggregated form of a presynaptic protein, α-synuclein (α-Syn). However, the mechanisms of α-Syn aggregation and actual aggregated species responsible for the degeneration of dopaminergic neurons have not yet been resolved. Despite the fact that α-Syn aggregation in LBs and LNs is crucial and mutations of α-Syn are associated with early onset PD, it is really a challenging task to establish a correlation between α-Syn aggregation rate and PD pathogenesis. Regardless of strong genetic contribution, PD is mostly sporadic and familial forms of the disease represent only a minor part (<10%) of all cases. The complexity in PD further increases due to the involvement of several cellular factors in the pathogenesis of the disease as well as the environmental factors associated with the risk of developing PD. Therefore, effect of these factors on α-Syn aggregation pathway and how these factors modulate the properties of wild type (WT) as well as mutated α-Syn should be collectively taken into account. The present review specifically provides an overview of recent research on α-Syn aggregation pathways and its modulation by several cellular factors potentially relevant to PD pathogenesis. We also briefly discuss about effect of environmental risk factors on α-Syn aggregation.
Topics: Amino Acid Sequence; Animals; Glycosaminoglycans; Humans; Parkinson Disease; Polyamines; Protein Aggregates; alpha-Synuclein
PubMed: 27737778
DOI: 10.1016/j.ijbiomac.2016.10.021 -
International Journal of Molecular... Jun 2022α-Synuclein is a protein with a molecular weight of 14.5 kDa and consists of 140 amino acids encoded by the gene. Missense mutations and gene duplications in the gene... (Review)
Review
α-Synuclein is a protein with a molecular weight of 14.5 kDa and consists of 140 amino acids encoded by the gene. Missense mutations and gene duplications in the gene cause hereditary Parkinson's disease. Highly phosphorylated and abnormally aggregated α-synuclein is a major component of Lewy bodies found in neuronal cells of patients with sporadic Parkinson's disease, dementia with Lewy bodies, and glial cytoplasmic inclusion bodies in oligodendrocytes with multiple system atrophy. Aggregated α-synuclein is cytotoxic and plays a central role in the pathogenesis of the above-mentioned synucleinopathies. In a healthy brain, most α-synuclein is unphosphorylated; however, more than 90% of abnormally aggregated α-synuclein in Lewy bodies of patients with Parkinson's disease is phosphorylated at Ser129, which is presumed to be of pathological significance. Several kinases catalyze Ser129 phosphorylation, but the role of phosphorylation enzymes in disease pathogenesis and their relationship to cellular toxicity from phosphorylation are not fully understood in α-synucleinopathy. Consequently, this review focuses on the pathogenic impact of α-synuclein phosphorylation and its kinases during the neurodegeneration process in α-synucleinopathy.
Topics: Humans; Lewy Bodies; Parkinson Disease; Phosphorylation; Synucleinopathies; alpha-Synuclein
PubMed: 35682892
DOI: 10.3390/ijms23116216 -
Molecules (Basel, Switzerland) Nov 2020Alpha-synuclein (αS) is an extensively studied protein due to its involvement in a group of neurodegenerative disorders, including Parkinson's disease, and its... (Review)
Review
Alpha-synuclein (αS) is an extensively studied protein due to its involvement in a group of neurodegenerative disorders, including Parkinson's disease, and its documented ability to undergo aberrant self-aggregation resulting in the formation of amyloid-like fibrils. In dilute solution, the protein is intrinsically disordered but can adopt multiple alternative conformations under given conditions, such as upon adsorption to nanoscale surfaces. The study of αS-nanoparticle interactions allows us to better understand the behavior of the protein and provides the basis for developing systems capable of mitigating the formation of toxic aggregates as well as for designing hybrid nanomaterials with novel functionalities for applications in various research areas. In this review, we summarize current progress on αS-nanoparticle interactions with an emphasis on the conformational plasticity of the biomolecule.
Topics: Adsorption; Amyloid; Humans; Molecular Conformation; Nanoconjugates; Nanoparticles; Protein Aggregates; alpha-Synuclein
PubMed: 33260436
DOI: 10.3390/molecules25235625 -
Biological Chemistry Jan 2017Alpha-synuclein (α-syn) is an abundant neuronal protein whose physiological function, even if still not completely understood, has been consistently related to synaptic... (Review)
Review
Alpha-synuclein (α-syn) is an abundant neuronal protein whose physiological function, even if still not completely understood, has been consistently related to synaptic function and vesicle trafficking. A group of disorders known as synucleinopathies, among which Parkinson's disease (PD), is deeply associated with the misfolding and aggregation of α-syn, which can give rise to proteinaceous inclusion known as Lewy bodies (LB). Proteostasis stress is a relevant aspect in these diseases and, currently, the presence of oligomeric α-syn species rather than insoluble aggregated forms, appeared to be associated with cytotoxicity. Many observations suggest that α-syn is responsible for neurodegeneration by interfering with multiple signaling pathways. α-syn protein can directly form plasma membrane channels or modify with their activity, thus altering membrane permeability to ions, abnormally associate with mitochondria and cause mitochondrial dysfunction (i.e. mitochondrial depolarization, Ca2+ dys-homeostasis, cytochrome c release) and interfere with autophagy regulation. The picture is further complicated by the fact that single point mutations, duplications and triplication in α-syn gene are linked to autosomal dominant forms of PD. In this review we discuss the multi-faced aspect of α-syn biology and address the main hypothesis at the basis of its involvement in neuronal degeneration.
Topics: Animals; Extracellular Space; Humans; Intracellular Space; Mutation; Protein Aggregates; Protein Multimerization; alpha-Synuclein
PubMed: 27508962
DOI: 10.1515/hsz-2016-0201