ArticleHuman molecular genetics2021
Excess membrane binding of monomeric alpha-, beta- and gamma-synuclein is invariably associated with inclusion formation and toxicity.
Article in Human molecular genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 17 citations in OpenAlex.
- Quantifying the Acute Toxicity of Alpha-Synuclein Membrane-Accumulation in a Cell-Based Assay.Journal of molecular neuroscience : MN · 2026Article
- Elevation of Stearoyl-Coenzyme A Desaturase and Monounsaturated Fatty Acids in Parkinson's Disease Serum.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- Concentration-dependent mutational scanning probes the cellular folding landscape of α-synuclein in yeast.Protein science : a publication of the Protein Society · 2026Article
- Concentration-Dependent Mutational Scanning Probes the Cellular Folding Landscape of α-Synuclein in Yeast.bioRxiv : the preprint server for biology · 2025Article
- The Potential of β-Synuclein-Specific Regulatory T Cell Therapy as a Treatment for Progressive Multiple Sclerosis.International journal of molecular sciences · 2025Review
- Dysregulation of Monounsaturated Fatty Acids is Related to α-Synuclein in Multiple System Atrophy.Movement disorders : official journal of the Movement Disorder Society · 2025Article
- Increased burden of rare risk variants across gene expression networks predisposes to sporadic Parkinson's disease.Cell reports · 2025Article
- Research Priorities on the Role of α-Synuclein in Parkinson's Disease Pathogenesis.Movement disorders : official journal of the Movement Disorder Society · 2024Review
- Review
- Excess phosphoserine-129 α-synuclein induces synaptic vesicle trafficking and declustering defects at a vertebrate synapse.Molecular biology of the cell · 2024Article
- Synucleinopathies: Intrinsic and Extrinsic Factors.Cell biochemistry and biophysics · 2023Article
- Cancer in pathologically confirmed multiple system atrophy.Clinical autonomic research : official journal of the Clinical Autonomic Research Society · 2023Article
- The Synucleins and the Astrocyte.Biology · 2023Review
- Synucleins: New Data on Misfolding, Aggregation and Role in Diseases.Biomedicines · 2022Review
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
α-Synuclein (αS) has been well-documented to play a role in human synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). First, the lesions found in PD/DLB brains-Lewy bodies and Lewy neurites-are rich in aggregated αS. Second, genetic evidence links missense mutations and increased αS expression to familial forms of PD/DLB. Third, toxicity and cellular stress can be caused by αS under certain experimental conditions. In contrast, the homologs β-synuclein (βS) and γ-synuclein (γS) are not typically found in Lewy bodies/neurites, have not been clearly linked to brain diseases and have been largely non-toxic in experimental settings. In αS, the so-called non-amyloid-β component of plaques (NAC) domain, constituting amino acids 61-95, has been identified to be critical for aggregation in vitro. This domain is partially absent in βS and only incompletely conserved in γS, which could explain why both homologs do not cause disease. However, αS in vitro aggregation and cellular toxicity have not been firmly linked experimentally, and it has been proposed that excess αS membrane binding is sufficient to induce neurotoxicity. Indeed, recent characterizations of Lewy bodies have highlighted the accumulation of lipids and membranous organelles, raising the possibility that βS and γS could also become neurotoxic if they were more prone to membrane/lipid binding. Here, we increased βS and γS membrane affinity by strategic point mutations and demonstrate that these proteins behave like membrane-associated monomers, are cytotoxic and form round cytoplasmic inclusions that can be prevented by inhibiting stearoyl-CoA desaturase.
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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.