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Acta Neuropathologica Mar 2022Synucleinopathies are a group of clinically and neuropathologically distinct protein misfolding diseases caused by unique α-synuclein conformations, or strains. While... (Review)
Review
Synucleinopathies are a group of clinically and neuropathologically distinct protein misfolding diseases caused by unique α-synuclein conformations, or strains. While multiple atomic resolution cryo-electron microscopy structures of α-synuclein fibrils are now deposited in Protein Data Bank, significant gaps in the biological consequences arising from each conformation have yet to be unraveled. Mutations in the α-synuclein gene (SNCA), cofactors, and the solvation environment contribute to the formation and maintenance of each disease-causing strain. This review highlights the impact of each of these factors on α-synuclein misfolding and discusses the implications of the resulting structural variability on therapeutic development.
Topics: Biology; Cryoelectron Microscopy; Humans; Proteostasis Deficiencies; Synucleinopathies; alpha-Synuclein
PubMed: 35122113
DOI: 10.1007/s00401-022-02403-w -
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 -
Movement Disorders : Official Journal... Feb 2016Aggregation of alpha-synuclein is implicated in several neurodegenerative diseases collectively termed synucleinopathies. Emerging evidence strongly implicates... (Review)
Review
Aggregation of alpha-synuclein is implicated in several neurodegenerative diseases collectively termed synucleinopathies. Emerging evidence strongly implicates cell-to-cell transmission of misfolded alpha-synuclein as a common pathogenetic mechanism in synucleinopathies. The impact of alpha-synuclein pathology on neuronal dysfunction and behavioral impairments is being explored in animal models. This review provides an update on how research in animal models supports the concept that misfolded alpha-synuclein spreads from cell to cell and describes how findings in animal models might relate to the disease process in humans. Finally, we discuss the current underlying molecular and cellular mechanisms and future therapeutic strategies targeting alpha-synuclein propagation.
Topics: Animals; Disease Models, Animal; Neurodegenerative Diseases; alpha-Synuclein
PubMed: 26347034
DOI: 10.1002/mds.26370 -
Research Progress of α-Synuclein Aggregation Inhibitors for Potential Parkinson's Disease Treatment.Mini Reviews in Medicinal Chemistry 2023Parkinson's disease (PD) is characterized by fibrillation of disordered proteins known as Lewy bodies in the substantia nigra that also undergo progressive... (Review)
Review
INTRODUCTION
Parkinson's disease (PD) is characterized by fibrillation of disordered proteins known as Lewy bodies in the substantia nigra that also undergo progressive neurodegeneration. The aggregation of α-synuclein (α-syn) is a hallmark and potentially a critical step in the development of Parkinson's disease and other synucleinopathies. The synaptic vesicle protein α-syn is a small, abundant, highly conserved disordered protein and the causative agent of neurodegenerative diseases. Several novel pharmacologically active compounds are used to treat PD and other neurodegenerative disorders. Though, the mechanism through which these molecules inhibit the α-syn aggregation is still not fully understood.
OBJECTIVE
This review article is focused on the recent advancements in compounds that can inhibit the development of α-syn fibrillation and oligomerization.
METHODS
The current review article is based on the most recent and frequently cited papers from Google Scholar, SciFinder, and Researchgate sources.
DESCRIPTION
In the progression of PD, the mechanism of α-syn aggregation involves the structural transformation from monomers into amyloid fibrils. As the accumulation of α-syn in the brain has been linked to many disorders, the recent search for disease-modifying medications mainly focused on modifying the α-syn aggregation. This review contains a detailed report of literature findings and illustrates the unique structural features, structure-activity relationship, and therapeutic potential of the natural flavonoids in the inhibition of α-syn are also discussed.
CONCLUSION
Recently, many naturally occurring molecules such as curcumin, polyphenols, nicotine, EGCG, and stilbene have been recognized to inhibit the fibrillation and toxicity of α-syn. Therefore, knowing the α-synuclein filament's structure and how they originate will help invent particular biomarkers for synucleinopathies and develop reliable and effective mechanism-based therapeutics. We hope the information this review provides may help evaluate novel chemical compounds, such as α- syn aggregation inhibitors, and will contribute to developing novel drugs for treating Parkinson's disease.
Topics: Humans; Parkinson Disease; alpha-Synuclein; Synucleinopathies; Lewy Bodies; Neurodegenerative Diseases
PubMed: 37198991
DOI: 10.2174/1389557523666230517163501 -
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 -
Essays in Biochemistry Dec 2022α-Synuclein (α-Syn) is a natively unstructured protein, which self-assembles into higher-order aggregates possessing serious pathophysiological implications. α-Syn... (Review)
Review
α-Synuclein (α-Syn) is a natively unstructured protein, which self-assembles into higher-order aggregates possessing serious pathophysiological implications. α-Syn aberrantly self-assembles into protein aggregates, which have been widely implicated in Parkinson's disease (PD) pathogenesis and other synucleinopathies. The self-assembly of α-Syn involves the structural conversion of soluble monomeric protein into oligomeric intermediates and eventually fibrillar aggregates of amyloids with cross-β-sheet rich conformation. These aggregated α-Syn species majorly constitute the intraneuronal inclusions, which is a hallmark of PD neuropathology. Self-assembly/aggregation of α-Syn is not a single-state conversion process as unfolded protein can access multiple conformational states through the formation of metastable, transient pre-fibrillar intermediate species. Recent studies have indicated that soluble oligomers are the potential neurotoxic species responsible for cell death in PD pathogenesis. The heterogeneous and transient nature of oligomers formed during the early stage of aggregation pathway limit their detailed study in understanding the structure-toxicity relationship. Moreover, the precise molecular events occurring in the early stage of α-Syn aggregation process majorly remain unsolved. Recently, liquid-liquid phase separation (LLPS) of α-Syn has been designated as an alternate nucleation mechanism, which occurs in the early lag phase of the aggregation pathway leading to the formation of dynamic supramolecular assemblies. The stronger self-association among the protein molecules triggers the irreversible liquid-to-solid transition of these supramolecular assemblies into the amyloid-like hydrogel, which may serve as a reservoir entrapping toxic oligomeric intermediates and fibrils. This review strives to provide insights into different modes of α-Syn self-assemblies including LLPS-mediated self-assembly and its recent advancements.
Topics: Humans; alpha-Synuclein; Protein Aggregates; Parkinson Disease; Amyloid; Intrinsically Disordered Proteins
PubMed: 36373662
DOI: 10.1042/EBC20220055 -
Methods in Cell Biology 2022Alpha-synuclein (α-syn) is a natively unfolded protein that is abundantly expressed in the central nervous system. Although it has been shown to be involved in...
Alpha-synuclein (α-syn) is a natively unfolded protein that is abundantly expressed in the central nervous system. Although it has been shown to be involved in neurotransmission and cognition, its exact functions remain elusive. The misfolding of this protein into β-sheet-rich amyloid structures and subsequent aggregation has been associated with several neurodegenerative diseases, including Parkinson's disease. The interaction of α-syn with lipid membranes has been implicated in the formation of these pathological aggregates. At the same time, some physiological functions of α-syn also seem to require membrane interactions. A majority of the disease-associated mutations of α-syn occur in the lipid binding domain, further indicating the importance of membrane interactions in health and disease. A comprehensive understanding of the factors that modulate these interactions will help delineate the physiological and pathological states of this protein.
Topics: Lipids; Mutation; alpha-Synuclein
PubMed: 35623711
DOI: 10.1016/bs.mcb.2021.12.002 -
Brain Pathology (Zurich, Switzerland) May 2013Parkinson's disease is characterized by α-synuclein pathology in the form of Lewy bodies and Lewy neurites. Braak et al described the spatial and temporal spread of... (Review)
Review
Parkinson's disease is characterized by α-synuclein pathology in the form of Lewy bodies and Lewy neurites. Braak et al described the spatial and temporal spread of α-synuclein pathology in Parkinson's disease. Recent experimental studies have demonstrated that α-synuclein can transfer from cell to cell. In this review, we highlight the involvement of α-synuclein in Parkinson's disease and in Braak's staging of Parkinson's disease pathology. We discuss whether a prion-like mechanism of α-synuclein spread might contribute to Parkinson's disease pathology. We describe recent studies investigating cell-to-cell transfer of α-synuclein and focus our review on the long-distance axonal transport of α-synuclein along neurons.
Topics: Algorithms; Animals; Axonal Transport; Axons; Central Nervous System; Digestive System; Disease Progression; Humans; Parkinson Disease; Prions; alpha-Synuclein
PubMed: 23587141
DOI: 10.1111/bpa.12046 -
Neurobiology of Disease Jan 2018The deposition of misfolded β-sheet enriched amyloid protein is a shared feature of many neurodegenerative diseases. Recent studies demonstrated the existence of... (Review)
Review
The deposition of misfolded β-sheet enriched amyloid protein is a shared feature of many neurodegenerative diseases. Recent studies demonstrated the existence of conformationally diverse strains as a common property for multiple amyloidogenic proteins including α-Synuclein (α-Syn). α-Syn is misfolded and aggregated in a group of neurodegenerative diseases collectively known as α-Synucleinopathies, which include Parkinson's disease (PD), dementia with Lewy body, multiple system atrophy and also a subset of Alzheimer's disease patients with concomitant PD-like Lewy bodies and neurites. While sharing the same pathological protein, different α-Synucleinopathies demonstrate distinct clinical and pathological phenotypes, which could result from the existence of diverse pathological α-Syn strains in patients. In this review, we summarized the characteristics of different α-Synucleinopathies and α-Syn strains generated with recombinant α-Syn monomers. We also make predictions of α-Syn strains that could potentially exist in patients based on the knowledge from other amyloid proteins and the clinical and pathological features of different α-Synucleinopathies.
Topics: Animals; Humans; Neurodegenerative Diseases; Protein Aggregation, Pathological; Protein Conformation; alpha-Synuclein
PubMed: 28751258
DOI: 10.1016/j.nbd.2017.07.018 -
Progress in Brain Research 2020Alpha-synuclein (aSyn) was identified as the main component of inclusions that define synucleinopathies more than 20 years ago. Since then, aSyn has been extensively... (Review)
Review
Alpha-synuclein (aSyn) was identified as the main component of inclusions that define synucleinopathies more than 20 years ago. Since then, aSyn has been extensively studied in an attempt to unravel its roles in both physiology and pathology. Today, studying the mechanisms of aSyn toxicity remains in the limelight, leading to the identification of novel pathways involved in pathogenesis. In this chapter, we address the molecular mechanisms involved in synucleinopathies, from aSyn misfolding and aggregation to the various cellular effects and pathologies associated. In particular, we review our current understanding of the mechanisms involved in the spreading of aSyn between different cells, from the periphery to the brain, and back. Finally, we also review recent studies on the contribution of inflammation and the gut microbiota to pathology in synucleinopathies. Despite significant advances in our understanding of the molecular mechanisms involved, we still lack an integrated understanding of the pathways leading to neurodegeneration in PD and other synucleinopathies, compromising our ability to develop novel therapeutic strategies.
Topics: Animals; Humans; Inflammation; Microbiota; Synucleinopathies; alpha-Synuclein
PubMed: 32247376
DOI: 10.1016/bs.pbr.2019.10.005