In situ amplification of α-synuclein amyloid fibril reveals a distinct polymorph related to Parkinson's disease and dementia with Lewy body.
In situ amplification of α-synuclein amyloid fibril reveals a distinct polymorph related to Parkinson's disease and dementia with Lewy body.
Where did the research take place?
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Shanghai, CN · Author affiliation
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China; Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai 200240, China.Location evidence
Hefei, CN · Author affiliation
Department of Neurology, Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Neurodegenerative Disorder Research Center, Anhui Province Key Laboratory of Biomedical Aging Research, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.Location evidence
Beijing, CN · Author affiliation
Department of Human Anatomy, Histology and Embryology, Institute of Basic Medical Sciences, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing 100005, China.Location evidence
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Original abstract
High-resolution structure determination of ex vivo amyloid fibrils offers critical mechanistic insights into amyloid polymorphism and heterogeneity of neurodegenerative diseases. However, purifying amyloid fibrils from diseased brains may favor certain polymorphs over others. Here, instead of purifying fibrils, we used in situ amplification (ISA) of α-synuclein (α-syn) fibrils in brain homogenates. Cryoelectron microscopy (cryo-EM) structural analysis of the ISA fibrils from patients with Parkinson's disease (PD) or dementia with Lewy bodies (DLB) reveal polymorphic fibril ensembles of each case including fibrils with morphologies similar to previously reported Lewy fold, as well as many others. Remarkably, we determine the high-resolution structure of a distinct polymorph (ISA-P1) that differs from the Lewy fold but is similar to those of multiple system atrophy (MSA) and juvenile-onset synucleinopathy (JOS). Our work supports the existence of alternative α-syn fibril polymorphs in PD and DLB, some of which may share common prototypical folds across various synucleinopathies.