ArticleMovement disorders : official journal of the Movement Disorder Society2020
Structurally distinct α-synuclein fibrils induce robust parkinsonian pathology.
Article in Movement disorders : official journal of the Movement Disorder Society, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 35 citations in OpenAlex.
- Genetics of α-Synuclein: The Prime Pathological Player of Parkinson's Disease.Neurotoxicity research · 2026Review
- Hidden faces of alpha-synuclein: Cryo-EM revelation of fibril polymorphs driven by disease, mutations, and PTMs.BBA advances · 2026Review
- Glycine-to-aspartic acid mutation at codon 51 inBrain communications · 2025Article
- Pathological mechanisms and treatment of sporadic Parkinson's disease: past, present, and future.Journal of neural transmission (Vienna, Austria : 1996) · 2024Review
- α-Synuclein: A Promising Biomarker for Parkinson's Disease and Related Disorders.Journal of movement disorders · 2024Article
- Lysophagy protects against propagation of α-synuclein aggregation through ruptured lysosomal vesicles.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- The G51D SNCA mutation generates a slowly progressive α-synuclein strain in early-onset Parkinson's disease.Acta neuropathologica communications · 2023Article
- Cryo-EM structure of amyloid fibril formed by α-synuclein hereditary A53E mutation reveals a distinct protofilament interface.The Journal of biological chemistry · 2023Article
- Effects of Mutations and Post-Translational Modifications on α-Synuclein In Vitro Aggregation.Journal of molecular biology · 2022Review
- Untwisted α-Synuclein Filaments Formed in the Presence of Lipid Vesicles.Biochemistry · 2022Article
- The hereditary mutation G51D unlocks a distinct fibril strain transmissible to wild-type α-synuclein.Nature communications · 2021Article
- Studying the effect of alpha-synuclein and Parkinson's disease linked mutants on inter pathway connectivities.Scientific reports · 2021Article
- 14-3-3 mitigates alpha-synuclein aggregation and toxicity in the in vivo preformed fibril model.Acta neuropathologica communications · 2021Article
- The emerging role of α-synuclein truncation in aggregation and disease.The Journal of biological chemistry · 2020Review
- Pathogenic Mutations Differentially Regulate Cell-to-Cell Transmission of α-Synuclein.Frontiers in cellular neuroscience · 2020Article
- α-Synuclein conformational strains spread, seed and target neuronal cells differentially after injection into the olfactory bulb.Acta neuropathologica communications · 2019Article
- A Summary of Phenotypes Observed in the In Vivo Rodent Alpha-Synuclein Preformed Fibril Model.Journal of Parkinson's diseaseReview
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14 authors at 7 institutions in 2 countries.
Funding
Abstract
objectiveAlpha-synuclein (α-syn) is a major component of Lewy bodies, which are the pathological hallmark in Parkinson's disease, and its genetic mutations cause familial forms of Parkinson's disease. Patients with α-syn G51D mutation exhibit severe clinical symptoms. However, in vitro studies showed low propensity for α-syn with the G51D mutation. We studied the mechanisms associated with severe neurotoxicity of α-syn G51D mutation using a murine model generated by G51D α-syn fibril injection into the brain.
methodsStructural analysis of wild-type and G51D α-syn-fibrils were performed using Fourier transform infrared spectroscopy. The ability of α-syn fibrils forming aggregates was first assessed in in vitro mammalian cells. An in vivo mouse model with an intranigral injection of α-syn fibrils was then used to evaluate the propagation pattern of α-syn and related cellular changes.
resultsWe found that G51D α-syn fibrils have higher β-sheet contents than wild-type α-syn fibrils. The addition of G51D α-syn fibrils to mammalian cells overexpressing α-syn resulted in the formation of phosphorylated α-syn inclusions at a higher rate. Similarly, an injection of G51D α-syn fibrils into the substantia nigra of a mouse brain induced more widespread phosphorylated α-syn pathology. Notably, the mice injected with G51D α-syn fibrils exhibited progressive nigral neuronal loss accompanied with mitochondrial abnormalities and motor impairment.
conclusionOur findings indicate that the structural difference of G51D α-syn fibrils plays an important role in the rapidly developed and more severe neurotoxicity of G51D mutation-linked Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.
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