ArticleActa neuropathologica2023
New SNCA mutation and structures of α-synuclein filaments from juvenile-onset synucleinopathy.
Article in Acta neuropathologica, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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58 citing papers in PubMed, 83 citations in OpenAlex.
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- α-Synuclein strain homogeneity in multiple system atrophy subtypes.Brain pathology (Zurich, Switzerland) · 2026Article
- Cryo-EM structures of biopsy-derived TTR fibrils in hereditary transthyretin amyloidosis.Nature communications · 2026Article
- In Vitro-Prepared A30P Alpha-Synuclein Fibrils Adopt the Conserved and Disease-Relevant Greek Key Fold.The journal of physical chemistry. B · 2026Article
- α-Synuclein aggregation landscape from phase separation to neurotoxic intermediates.FEBS letters · 2026Review
- A Biological Framework for Parkinson's Disease: Advances in α-Synuclein-Centered Biomarkers and Staging.Journal of neurochemistry · 2026Review
- Transthyretin amyloid fibrils adopt distinct folds in the brain.bioRxiv : the preprint server for biology · 2026Article
- Adaptation of α-synuclein fibrils following multiple system atrophy transmission to mice.bioRxiv : the preprint server for biology · 2026Article
- Early α-synuclein-mediated mitochondrial dysfunction in a human cell model of Parkinson's disease dementia.Communications biology · 2026Article
- PET imaging of alpha-synuclein: from radiotracer design through in vitro and in vivo translation.European journal of nuclear medicine and molecular imaging · 2026Review
- Mutational Scanning of α-Synuclein using a Clickable Protein Tag Reveals Determinants of Membrane-Induced Aggregation.bioRxiv : the preprint server for biology · 2026Article
- Distinct tau filament folds in familial frontotemporal dementia due to thebioRxiv : the preprint server for biology · 2026Article
- Article
- Formation of Condition-Dependent Alpha-Synuclein Fibril Strain in Artificial Cerebrospinal Fluid.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- When Proteins Go MAD-Misfolded, Amplified, Detected: Advances in α-Synuclein Pathophysiology and RT-QuIC Detection.Molecular neurobiology · 2026Review
- Propagation of α-synuclein pathology: models, mechanisms and future goals.Molecular neurodegeneration advances · 2026Review
- Hidden faces of alpha-synuclein: Cryo-EM revelation of fibril polymorphs driven by disease, mutations, and PTMs.BBA advances · 2026Review
- Prions and protein aggregates as pathogens, self-propagating structures, biomarkers, and therapeutic targets.Microbiology and molecular biology reviews : MMBR · 2025Review
- MAS Cryoprobe Enhances Solid-State NMR Signals of α-Synuclein Fibrils.bioRxiv : the preprint server for biology · 2025Article
- Alpha-Synuclein Neurobiology in Parkinson's Disease: A Comprehensive Review of Its Role, Mechanisms, and Therapeutic Perspectives.Brain sciences · 2025Review
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16 authors at 9 institutions in 5 countries.
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Abstract
A 21-nucleotide duplication in one allele of SNCA was identified in a previously described disease with abundant α-synuclein inclusions that we now call juvenile-onset synucleinopathy (JOS). This mutation translates into the insertion of MAAAEKT after residue 22 of α-synuclein, resulting in a protein of 147 amino acids. Both wild-type and mutant proteins were present in sarkosyl-insoluble material that was extracted from frontal cortex of the individual with JOS and examined by electron cryo-microscopy. The structures of JOS filaments, comprising either a single protofilament, or a pair of protofilaments, revealed a new α-synuclein fold that differs from the folds of Lewy body diseases and multiple system atrophy (MSA). The JOS fold consists of a compact core, the sequence of which (residues 36-100 of wild-type α-synuclein) is unaffected by the mutation, and two disconnected density islands (A and B) of mixed sequences. There is a non-proteinaceous cofactor bound between the core and island A. The JOS fold resembles the common substructure of MSA Type I and Type II dimeric filaments, with its core segment approximating the C-terminal body of MSA protofilaments B and its islands mimicking the N-terminal arm of MSA protofilaments A. The partial similarity of JOS and MSA folds extends to the locations of their cofactor-binding sites. In vitro assembly of recombinant wild-type α-synuclein, its insertion mutant and their mixture yielded structures that were distinct from those of JOS filaments. Our findings provide insight into a possible mechanism of JOS fibrillation in which mutant α-synuclein of 147 amino acids forms a nucleus with the JOS fold, around which wild-type and mutant proteins assemble during elongation.
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