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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 -
Translational Neurodegeneration Apr 2022Alpha-synuclein (α-syn) exhibits pathological misfolding in many human neurodegenerative disorders. We previously showed that α-syn is arginylated in the mouse brain...
BACKGROUND
Alpha-synuclein (α-syn) exhibits pathological misfolding in many human neurodegenerative disorders. We previously showed that α-syn is arginylated in the mouse brain and that lack of arginylation leads to neurodegeneration in mice.
METHODS
Here, we tested α-syn arginylation in human brain pathology using newly derived antibodies in combination with Western blotting, biochemical assays, and experiments in live neurons.
RESULTS
We found that α-syn was arginylated in the human brain on E46 and E83, two sites previously implicated in α-syn pathology and familial cases of Parkinson's disease. The levels of arginylation in different brain samples ranged between ~ 3% and ~ 50% of the total α-syn pool, and this arginylation nearly exclusively concentrated in the subcellular α-syn fraction that sedimented at low centrifugation speeds and appeared to be simultaneously targeted by multiple posttranslational modifications. Arginylated α-syn was less susceptible to S129 phosphorylation and pathological aggregation in neurons. The arginylation level inversely correlated with the overall α-syn levels and with patient age, suggesting a possible causal relationship between arginylation decline and α-syn-dependent neuropathology.
CONCLUSION
We propose that α-syn arginylation constitutes a potential neuroprotective mechanism that prevents its abnormal accumulation during neurodegeneration and aging in the human brain.
Topics: Animals; Brain; Humans; Mice; Neurodegenerative Diseases; Parkinson Disease; Synucleinopathies; alpha-Synuclein
PubMed: 35395956
DOI: 10.1186/s40035-022-00295-0 -
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 -
Current Neuropharmacology 2016Alpha-Synuclein is found in the neuronal cells but its native function is not well known. While α -synuclein is an intrinsically disordered protein that adopts a... (Review)
Review
Alpha-Synuclein is found in the neuronal cells but its native function is not well known. While α -synuclein is an intrinsically disordered protein that adopts a helical conformation upon membrane binding, numerous studies have shown that oligomeric β-forms of this protein are cytotoxic. This response to misfolded species contributes to Parkinson's Disease etiology and symptoms. The resulting amyloid fibrils are an established diagnostic in Parkinson's Disease. In this review, we focus on strategies that have been used to inhibit the amyloidogenesis of α -synuclein either by stabilizing the native state, or by redirecting the pathway to less toxic aggregates. Small molecules such as polyphenols, peptides as well as large proteins have proven effective at protecting cells against the cytotoxicity of α-synuclein. These strategies may lead to the development of therapeutic agents that could prove useful in combating this disease.
Topics: Amyloid; Amyloidosis; Animals; Humans; Mutation; Parkinson Disease; Protein Folding; alpha-Synuclein
PubMed: 26517049
DOI: 10.2174/1570159x13666151030103153 -
Seminars in Cell & Developmental Biology Mar 2020α-synuclein and Tau are proteins prone to pathological misfolding and aggregation that are normally found in the presynaptic and axonal compartments of neurons.... (Review)
Review
α-synuclein and Tau are proteins prone to pathological misfolding and aggregation that are normally found in the presynaptic and axonal compartments of neurons. Misfolding initiates a homo-oligomerization and aggregation cascade culminating in cerebral accumulation of aggregated α-synuclein and Tau in insoluble protein inclusions in multiple neurodegenerative diseases. Traditionally, α-synuclein-containing Lewy bodies have been associated with Parkinson's disease and Tau-containing neurofibrillary tangles with Alzheimer's disease and various frontotemporal dementia syndromes. However, there is significant overlap and co-occurrence of α-synuclein and Tau pathologies in a spectrum of neurodegenerative diseases. Importantly, α-synuclein and Tau can interact in cells, and their pathological conformations are capable of templating further misfolding and aggregation of each other. They also share a number of protein interactors indicating that network perturbations may contribute to chronic proteotoxic stress and neuronal dysfunction in synucleinopathies and tauopathies, some of which share similarities in both neuropathological and clinical manifestations. In this review, we focus on the protein interactions of these two pathologically important proteins and consider a network biology perspective towards neurodegenerative diseases.
Topics: Animals; Humans; Neurodegenerative Diseases; alpha-Synuclein; tau Proteins
PubMed: 29738880
DOI: 10.1016/j.semcdb.2018.05.005 -
Chemistry and Physics of Lipids Mar 2021Parkinson's disease (PD) is the second most common neurodegenerative disease. Currently, PD has no treatment. The neuronal protein α-synuclein (αS) plays an important... (Review)
Review
Parkinson's disease (PD) is the second most common neurodegenerative disease. Currently, PD has no treatment. The neuronal protein α-synuclein (αS) plays an important role in PD. However, the molecular mechanisms governing its physiological and pathological roles are not fully understood. It is becoming widely acknowledged that the biological roles of αS involve interactions with biological membranes. In these biological processes there is a fine-tuned interplay between lipids affecting the properties of αS and αS affecting lipid metabolism, αS binding to membranes, and membrane damage. In this review, the intricate interactions between αS and membranes will be reviewed and a discussion of the relationship between αS and neuronal membrane structural plasticity in health and disease will be made. It is proposed that in healthy neurons the conformational flexibilities of αS and the neuronal membranes are coupled to assist the physiological roles of αS. However, in circumstances where their conformational flexibilities are decreased or uncoupled, there is a shift toward cell toxicity. Strategies to modulate toxic αS-membrane interactions are potential approaches for the development of new therapies for PD. Future work using specific αS molecular species as well as membranes with specific physicochemical properties should widen our understanding of the intricate biological roles of αS which, in turn, would propel the development of new strategies for the treatment of PD.
Topics: Cell Membrane; Humans; Molecular Conformation; Neurodegenerative Diseases; Neurons; alpha-Synuclein
PubMed: 33434528
DOI: 10.1016/j.chemphyslip.2020.105034 -
Brain Pathology (Zurich, Switzerland) May 2016α-synuclein is normally situated in the nerve terminal but it accumulates and aggregates in axons and cell bodies in synucleinopathies such as Parkinson's disease. The... (Review)
Review
α-synuclein is normally situated in the nerve terminal but it accumulates and aggregates in axons and cell bodies in synucleinopathies such as Parkinson's disease. The conformational changes occurring during α-synucleins aggregation process affects its interactions with other proteins and its subcellular localization. This review focuses on interaction partners of α-synuclein within different compartments of the cell with a focus on those preferentially binding aggregated α-synuclein. The aggregation state of α-synuclein also affects its catabolism and we hypothesize impaired macroautophagy is involved neuronal excretion of α-synuclein species responsible for the prion-like spreading of α-synuclein pathology.
Topics: Animals; Humans; Neurodegenerative Diseases; alpha-Synuclein
PubMed: 26940507
DOI: 10.1111/bpa.12374 -
Biochimica Et Biophysica Acta Jul 2016We review experimental and simulation approaches that have been used to determine curvature generation and remodeling of lipid bilayers by membrane-bending proteins.... (Review)
Review
We review experimental and simulation approaches that have been used to determine curvature generation and remodeling of lipid bilayers by membrane-bending proteins. Particular emphasis is placed on the complementary approaches used to study α-Synuclein (αSyn), a major protein involved in Parkinson's disease (PD). Recent cellular and biophysical experiments have shown that the protein 1) deforms the native structure of mitochondrial and model membranes; and 2) inhibits vesicular fusion. Today's advanced experimental and computational technology has made it possible to quantify these protein-induced changes in membrane shape and material properties. Collectively, experiments, theory and multi-scale simulation techniques have established the key physical determinants of membrane remodeling and rigidity: protein binding energy, protein partition depth, protein density, and membrane tension. Despite the exciting and significant progress made in recent years in these areas, challenges remain in connecting biophysical insights to the cellular processes that lead to disease. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov.
Topics: Binding Sites; Computer Simulation; Lipid Bilayers; Membrane Fluidity; Membrane Proteins; Models, Chemical; Molecular Dynamics Simulation; Protein Binding; Protein Conformation; Protein Interaction Mapping; alpha-Synuclein
PubMed: 26972046
DOI: 10.1016/j.bbamem.2016.03.012 -
Journal of Neurochemistry Apr 2020Protein aggregation plays a central role in numerous neurodegenerative diseases. The key proteins in these diseases are of significant importance, but their...
Disentangling aggregation-prone proteins: a new method for isolating α-synuclein species: An Editorial Highlight for "A simple, versatile and robust centrifugation-based filtration protocol for the isolation and quantification of α-synuclein monomers, oligomers and fibrils: Towards improving...
Protein aggregation plays a central role in numerous neurodegenerative diseases. The key proteins in these diseases are of significant importance, but their investigation can be challenging due to unique properties of protein misfolding and oligomerization. Alpha-synuclein protein (α-Syn) is the predominant component of Lewy Bodies in Parkinson's disease (PD) and is a member of this class of proteins. Many α-Syn studies are limited by the inability to separate various monomeric, oligomeric, and fibrillar forms of the protein from heterogeneous mixtures. This Editorial Highlight summarizes the impact of a study published in the current issue of Journal of Neurochemistry, in which Lashuel and colleagues developed a simple, rapid centrifugation- and filter-based method for separating, isolating, and quantifying different forms of α-Syn. The researchers used electron microscopy, SDS-PAGE, circular dichroism, and protein assays to carefully validate the method and quantitate α-Syn yields and loss. The publication of this new method will not only aid in future studies of α-Syn, but will likely extend to other proteins that underlie a variety of neurodegenerative diseases.
Topics: Centrifugation; Filtration; Humans; Parkinson Disease; Protein Aggregation, Pathological; Reproducibility of Results; alpha-Synuclein
PubMed: 32037541
DOI: 10.1111/jnc.14973 -
The Journal of Biological Chemistry Jun 2019The misfolding and aggregation of α-synuclein (αsyn) in the central nervous system is associated with a group of neurodegenerative disorders referred to as the... (Review)
Review
The misfolding and aggregation of α-synuclein (αsyn) in the central nervous system is associated with a group of neurodegenerative disorders referred to as the synucleinopathies. In addition to being a pathological hallmark of disease, it is now well-established that upon misfolding, αsyn acquires pathogenic properties, such as neurotoxicity, that can contribute to disease development. The mechanisms that produce αsyn misfolding and the molecular events underlying the neuronal damage caused by these misfolded species are not well-defined. A consistent observation that may be relevant to αsyn's pathogenicity is its ability to associate with lipids. This appears important not only to how αsyn aggregates, but also to the mechanism by which the misfolded protein causes intracellular damage. This review discusses the current literature reporting a role of lipids in αsyn misfolding and neurotoxicity in various synucleinopathy disorders and provides an overview of current methods to assess protein misfolding and pathogenicity both and .
Topics: Central Nervous System; Fatty Acids, Unsaturated; Humans; Lipids; Protein Aggregation, Pathological; Proteostasis Deficiencies; alpha-Synuclein
PubMed: 31064841
DOI: 10.1074/jbc.REV119.007500