ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2015
Definition of a molecular pathway mediating α-synuclein neurotoxicity.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 134 papers, 1 of them a synthesis that pooled it.
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Who cites it
134 citing papers in PubMed, 1 synthesis or guideline pooled it, 192 citations in OpenAlex.
- Pre-clinical Studies Identifying Molecular Pathways of Neuroinflammation in Parkinson's Disease: A Systematic Review.Frontiers in aging neuroscience · 2022Pooled it
- Low-Dose Ionizing Radiation and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Review of Recent Evidence and Future Research Directions Toward the Elucidation of a Metabolic, Immunologic, and Signaling Cascade.International journal of molecular sciences · 2026Review
- Synaptic vesicle architecture modulates α-synuclein conformation and pathogenic transitions in Parkinson's disease.Bioscience reports · 2026Review
- The Influence of Gut Microbiome on Alpha-Synuclein Aggregation: Implications for Parkinson's Disease Pathogenesis.Molecular neurobiology · 2026Review
- Cis-Acting Chaperoning by Macromolecular Tethering: A Built-In Layer of Cellular Chaperoning.International journal of molecular sciences · 2026Review
- Neuroprotective Effects of the Combination of Green Tea, Saffron, Docosahexaenoic Acid, and α-Lipoic Acid in an In Vitro Model of Parkinson's Disease.Molecular neurobiology · 2026Article
- Synphilin-1 modulates alpha-synuclein assembly, release and uptake.NPJ Parkinson's disease · 2025Article
- Aggregation and Propagation of α-Synuclein in Parkinson's Disease: A Bibliometric Perspective.Brain and behavior · 2025Article
- MicroRNAs and synaptic dysfunction in Parkinson's disease.Molecular therapy. Nucleic acids · 2025Review
- Clinical insights into catechin-based nanomedicine: a review of therapeutic potential in neurodegenerative diseases.3 Biotech · 2025Review
- The Rab3 family proteins in age-related neurodegeneration: unraveling molecular pathways and potential therapeutic targets.npj aging · 2025Review
- Synaptic vesicle-omics in mice captures signatures of aging and synucleinopathy.Nature communications · 2025Article
- Alpha-Synuclein Pathophysiology in Neurodegenerative Disorders: A Review Focusing on Molecular Mechanisms and Treatment Advances in Parkinson's Disease.Cellular and molecular neurobiology · 2025Review
- Chitosan-enhanced sensitivity of mercaptoundecanoic acid (MUA)- capped gold nanorod based localized surface plasmon resonance (LSPR) biosensor for detection of alpha-synuclein oligomer biomarker in parkinson's disease.Biotechnology and applied biochemistry · 2025Article
- Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin.Nature communications · 2025Article
- Astrocyte alterations in α-synucleinopathies.Frontiers in cellular neuroscience · 2025Review
- VAMP2 chaperones α-synuclein in synaptic vesicle co-condensates.Nature cell biology · 2024Article
- Review
- How Parkinson's Disease-Linked LRRK2 Mutations Affect Different CNS Cell Types.Journal of Parkinson's disease · 2024Review
- Excess phosphoserine-129 α-synuclein induces synaptic vesicle trafficking and declustering defects at a vertebrate synapse.Molecular biology of the cell · 2024Article
74 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
3 authors at 3 institutions in 1 country.
Funding
Abstract
α-Synuclein physiologically chaperones SNARE-complex assembly at the synapse but pathologically misfolds into neurotoxic aggregates that are characteristic for neurodegenerative disorders, such as Parkinson's disease, and that may spread from one neuron to the next throughout the brain during Parkinson's disease pathogenesis. In normal nerve terminals, α-synuclein is present in an equilibrium between a cytosolic form that is natively unfolded and monomeric and a membrane-bound form that is composed of an α-helical multimeric species that chaperones SNARE-complex assembly. Although the neurotoxicity of α-synuclein is well established, the relationship between the native conformations of α-synuclein and its pathological aggregation remain incompletely understood; most importantly, it is unclear whether α-synuclein aggregation originates from its monomeric cytosolic or oligomeric membrane-bound form. Here, we address this question by introducing into α-synuclein point mutations that block membrane binding and by then assessing the effect of blocking membrane binding on α-synuclein aggregation and neurotoxicity. We show that membrane binding inhibits α-synuclein aggregation; conversely, blocking membrane binding enhances α-synuclein aggregation. Stereotactic viral expression of wild-type and mutant α-synuclein in the substantia nigra of mice demonstrated that blocking α-synuclein membrane binding significantly enhanced its neurotoxicity in vivo. Our data delineate a folding pathway for α-synuclein that ranges from a physiological multimeric, α-helical, and membrane-bound species that acts as a SNARE-complex chaperone over a monomeric, natively unfolded form to an amyloid-like aggregate that is neurotoxic in vivo.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.