Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 20, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2012435118
Keywords
alpha-synuclein; Parkinson's diseases; E46K mutant; cryo-electron microscopy; pathology
Categories
Funding
- Major State Basic Research Development Program [2019YFE0120600]
- National Natural Science Foundation (NSF) of China [91853113, 31872716, 31800709, 32070963]
- Science and Technology Commission of Shanghai Municipality [18JC1420500]
- Shanghai Municipal Education Commission
- Shanghai Municipal Science and Technology Major Project [2019SHZDZX02]
- Shanghai Science and Technology Committee [20XD1425000]
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Our research has shown that WT mice inoculated with the human E46K mutant alpha-syn fibril (hE46K) strain exhibit early-onset motor deficits and morphologically different alpha-syn aggregation compared to those inoculated with the human WT fibril (hWT) strain. Cryoelectron microscopy has revealed that the hE46K strain induces both human and mouse WT alpha-syn monomers to form the fibril structure of the hE46K strain at the near-atomic level. Furthermore, the induced hWT strain inherits most of the pathological traits of the hE46K strain, suggesting that mutant strains' structural and pathological features could be propagated by the WT alpha-syn and amplified in familial Parkinson's diseases.
Heterozygous point mutations of alpha-synuclein (alpha-syn) have been linked to the early onset and rapid progression of familial Parkinson's diseases (fPD). However, the interplay between hereditary mutant and wild-type (WT) alpha-syn and its role in the exacerbated pathology of alpha-syn in fPD progression are poorly understood. Here, we find that WT mice inoculated with the human E46K mutant alpha-syn fibril (hE46K) strain develop early-onset motor deficit and morphologically different alpha-syn aggregation compared with those inoculated with the human WT fibril (hWT) strain. By using cryoelectron microscopy, we reveal at the near-atomic level that the hE46K strain induces both human and mouse WT alpha-syn monomers to form the fibril structure of the hE46K strain. Moreover, the induced hWT strain inherits most of the pathological traits of the hE46K strain as well. Our work suggests that the structural and pathological features of mutant strains could be propagated by the WT alpha-syn in such a way that the mutant pathology would be amplified in fPD.
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