{"doi":"10.1007/s00401-023-02550-8","title":"New SNCA mutation and structures of α-synuclein filaments from juvenile-onset synucleinopathy","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.","journal":"Acta Neuropathologica","year":2023,"id":316646,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":96,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9247,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":342603,"name":"Holly J. Garringer","orcid":"0000-0002-1899-7676","position":1,"is_corresponding":false},{"id":263374,"name":"Yang Shi","orcid":"0000-0001-9713-1709","position":2,"is_corresponding":false},{"id":818304,"name":"Sofia Lövestam","orcid":"0000-0002-2152-1476","position":3,"is_corresponding":false},{"id":331722,"name":"Sew‐Yeu Peak‐Chew","orcid":"0000-0002-7602-6384","position":4,"is_corresponding":false},{"id":839327,"name":"Xianjun Zhang","orcid":"0000-0003-3554-780X","position":5,"is_corresponding":false},{"id":277728,"name":"Abhay Kotecha","orcid":"0000-0002-4480-5439","position":6,"is_corresponding":false},{"id":842445,"name":"Mehtap Bacioglu","orcid":"0000-0003-0304-7026","position":7,"is_corresponding":false},{"id":994629,"name":"Atsuo Koto","orcid":null,"position":8,"is_corresponding":false},{"id":818306,"name":"Masaki Takao","orcid":"0000-0002-5392-996X","position":9,"is_corresponding":false},{"id":629913,"name":"Maria Grazia Spillantini","orcid":"0000-0002-8544-7332","position":10,"is_corresponding":false},{"id":268832,"name":"Bernardino Ghetti","orcid":"0000-0002-1842-8019","position":11,"is_corresponding":false},{"id":271115,"name":"Rubén Vidal","orcid":"0000-0002-5803-3871","position":12,"is_corresponding":false},{"id":117572,"name":"Alexey G. Murzin","orcid":null,"position":13,"is_corresponding":false},{"id":614851,"name":"Sjors H. W. Scheres","orcid":"0000-0002-0462-6540","position":14,"is_corresponding":false},{"id":71017,"name":"Michel Goedert","orcid":"0000-0002-5214-7886","position":15,"is_corresponding":false},{"id":990262,"name":"Yang Yang","orcid":"0000-0001-6827-7944","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T01:06:44.698773Z","pmid":"36847833","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}