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| Title | New SNCA mutation and structures of α-synuclein filaments from juvenile-onset synucleinopathy. |
|---|---|
| Journal, issue, pages | Acta Neuropathol, Vol. 145, Issue 5, Page 561-572, Year 2023 |
| Publish date | Feb 27, 2023 |
 Authors | Yang Yang / Holly J Garringer / Yang Shi / Sofia Lövestam / Sew Peak-Chew / Xianjun Zhang / Abhay Kotecha / Mehtap Bacioglu / Atsuo Koto / Masaki Takao / Maria Grazia Spillantini / Bernardino Ghetti / Ruben Vidal / Alexey G Murzin / Sjors H W Scheres / Michel Goedert /      |
| PubMed 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 ...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. |
 External links | Acta Neuropathol / PubMed:36847833 / PubMed Central |
| Methods | EM (helical sym.) |
| Resolution | 2.0 - 3.6 Å |
| Structure data | EMDB-16188, PDB-8bqv: EMDB-16189, PDB-8bqw: EMDB-16600, PDB-8ce7: EMDB-16603, PDB-8ceb:  EMDB-16604: Alpha-synuclein filament assembled in vitro with mutant (7 residues insertion) protein  EMDB-16608: WT alpha-synuclein filament assembled in vitro |
| Chemicals |  ChemComp-HOH: |
| Source |
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 Keywords | PROTEIN FIBRIL /  alpha-synuclein / amyloid / fibril / insertion / juvenile-onset synucleinopathy (JOS) / synucleinopathy / mutation / in vitro / recombinant |
