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Browsing by Author "Zhang, Xianjun"
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Item New SNCA mutation and structures of α-synuclein filaments from juvenile-onset synucleinopathy(Springer, 2023) Yang, Yang; Garringer, Holly J.; Shi, Yang; Lövestam, Sofia; Peak‑Chew, Sew; Zhang, Xianjun; Kotecha, Abhay; Bacioglu, Mehtap; Koto, Atsuo; Takao, Masaki; Grazia Spillantini, Maria; Ghetti, Bernardino; Vidal, Ruben; Murzin, Alexey G.; Scheres, Sjors H. W.; Goedert, Michel; Pathology and Laboratory Medicine, School of MedicineA 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.Item Structures of α-synuclein filaments from human brains with Lewy pathology(Springer Nature, 2022) Yang, Yang; Shi, Yang; Schweighauser, Manuel; Zhang, Xianjun; Kotecha, Abhay; Murzin, Alexey G.; Garringer, Holly J.; Cullinane, Patrick W.; Saito, Yuko; Foroud, Tatiana; Warner, Thomas T.; Hasegawa, Kazuko; Vidal, Ruben; Murayama, Shigeo; Revesz, Tamas; Ghetti, Bernardino; Hasegawa, Masato; Lashley, Tammaryn; Scheres, Sjors H.W.; Goedert, Michel; Pathology and Laboratory Medicine, School of MedicineParkinson's disease (PD) is the most common movement disorder, with resting tremor, rigidity, bradykinesia and postural instability being major symptoms1. Neuropathologically, it is characterized by the presence of abundant filamentous inclusions of α-synuclein in the form of Lewy bodies and Lewy neurites in some brain cells, including dopaminergic nerve cells of the substantia nigra2. PD is increasingly recognised as a multisystem disorder, with cognitive decline being one of its most common non-motor symptoms. Many patients with PD develop dementia more than 10 years after diagnosis3. PD dementia (PDD) is clinically and neuropathologically similar to dementia with Lewy bodies (DLB), which is diagnosed when cognitive impairment precedes parkinsonian motor signs or begins within one year from their onset4. In PDD, cognitive impairment develops in the setting of well-established PD. Besides PD and DLB, multiple system atrophy (MSA) is the third major synucleinopathy5. It is characterized by the presence of abundant filamentous α-synuclein inclusions in brain cells, especially oligodendrocytes (Papp-Lantos bodies). We previously reported the electron cryo-microscopy structures of two types of α-synuclein filament extracted from the brains of individuals with MSA6. Each filament type is made of two different protofilaments. Here we report that the cryo-electron microscopy structures of α-synuclein filaments from the brains of individuals with PD, PDD and DLB are made of a single protofilament (Lewy fold) that is markedly different from the protofilaments of MSA. These findings establish the existence of distinct molecular conformers of assembled α-synuclein in neurodegenerative disease.