ArticleProceedings of the National Academy of Sciences of the United States of America2016
Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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43 citing papers in PubMed, 89 citations in OpenAlex.
- Propagation of α-synuclein pathology: models, mechanisms and future goals.Molecular neurodegeneration advances · 2026Review
- Comparative Analysis of Aggregation of β- and γ-Synucleins in Vertebrates.Biomolecules · 2025Article
- Glutamatergic synaptic resilience to overexpressed human alpha-synuclein.NPJ Parkinson's disease · 2025Article
- α-Synuclein Pathology in Synucleinopathies: Mechanisms, Biomarkers, and Therapeutic Challenges.International journal of molecular sciences · 2025Review
- Emerging targets of α-synuclein spreading in α-synucleinopathies: a review of mechanistic pathways and interventions.Molecular neurodegeneration · 2025Review
- Nuclear alpha-synuclein accelerates cell senescence and neurodegeneration.Immunity & ageing : I & A · 2024Article
- A Perspective on Interdicting in Protein Misfolding for Therapeutic Drug Design: Modulating the Formation of Nonlocal Contacts in α-Synuclein as a Strategy against Parkinson's Disease.The journal of physical chemistry. B · 2024Review
- Sex-specific biphasic alpha-synuclein response and alterations of interneurons in a COVID-19 hamster model.EBioMedicine · 2024Article
- Copper ion incorporation in α-synuclein amyloids.Protein science : a publication of the Protein Society · 2024Article
- Review
- Aggregated Alpha-Synuclein Inclusions within the Nucleus Predict Impending Neuronal Cell Death in a Mouse Model of Parkinsonism.International journal of molecular sciences · 2022Article
- The Neurodegenerative Elderly Syndrome (NES) hypothesis: Alzheimer and Parkinson are two faces of the same disease.IBRO neuroscience reports · 2022Review
- Revisiting the specificity and ability of phospho-S129 antibodies to capture alpha-synuclein biochemical and pathological diversity.NPJ Parkinson's disease · 2022Article
- α-synucleinopathy exerts sex-dimorphic effects on the multipurpose DNA repair/redox protein APE1 in mice and humans.Progress in neurobiology · 2022Article
- Translocation of Distinct Alpha Synuclein Species from the Nucleus to Neuronal Processes during Neuronal Differentiation.Biomolecules · 2022Article
- A NAC domain mutation (E83Q) unlocks the pathogenicity of human alpha-synuclein and recapitulates its pathological diversity.Science advances · 2022Article
- Effects of oligomer toxicity, fibril toxicity and fibril spreading in synucleinopathies.Cellular and molecular life sciences : CMLS · 2022Review
- Receptor-Dependent Endocytosis Mediates α-Synuclein Oligomer Transport Into Red Blood Cells.Frontiers in aging neuroscience · 2022Article
- Acetylation Rather than H50Q Mutation Impacts the Kinetics of Cu(II) Binding to α-Synuclein.Chemphyschem : a European journal of chemical physics and physical chemistry · 2021Article
- CK1BP Reduces α-Synuclein Oligomerization and Aggregation Independent of Serine 129 Phosphorylation.Cells · 2021Article
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18 authors at 9 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Synucleinopathies are a group of progressive disorders characterized by the abnormal aggregation and accumulation of α-synuclein (aSyn), an abundant neuronal protein that can adopt different conformations and biological properties. Recently, aSyn pathology was shown to spread between neurons in a prion-like manner. Proteins like aSyn that exhibit self-propagating capacity appear to be able to adopt different stable conformational states, known as protein strains, which can be modulated both by environmental and by protein-intrinsic factors. Here, we analyzed these factors and found that the unique combination of the neurodegeneration-related metal copper and the pathological H50Q aSyn mutation induces a significant alteration in the aggregation properties of aSyn. We compared the aggregation of WT and H50Q aSyn with and without copper, and assessed the effects of the resultant protein species when applied to primary neuronal cultures. The presence of copper induces the formation of structurally different and less-damaging aSyn aggregates. Interestingly, these aggregates exhibit a stronger capacity to induce aSyn inclusion formation in recipient cells, which demonstrates that the structural features of aSyn species determine their effect in neuronal cells and supports a lack of correlation between toxicity and inclusion formation. In total, our study provides strong support in favor of the hypothesis that protein aggregation is not a primary cause of cytotoxicity.
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