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- Title
C-terminal truncation modulates α-Synuclein's cytotoxicity and aggregation by promoting the interactions with membrane and chaperone.
- Authors
Zhang, Cai; Pei, Yunshan; Zhang, Zeting; Xu, Lingling; Liu, Xiaoli; Jiang, Ling; Pielak, Gary J.; Zhou, Xin; Liu, Maili; Li, Conggang
- Abstract
α-Synuclein (α-syn) is the main protein component of Lewy bodies, the major pathological hallmarks of Parkinson's disease (PD). C-terminally truncated α-syn is found in the brain of PD patients, reduces cell viability and tends to form fibrils. Nevertheless, little is known about the mechanisms underlying the role of C-terminal truncation on the cytotoxicity and aggregation of α-syn. Here, we use nuclear magnetic resonance spectroscopy to show that the truncation alters α-syn conformation, resulting in an attractive interaction of the N-terminus with membranes and molecular chaperone, protein disulfide isomerase (PDI). The truncated protein is more toxic to mitochondria than full-length protein and diminishes the effect of PDI on α-syn fibrillation. Our findings reveal a modulatory role for the C-terminus in the cytotoxicity and aggregation of α-syn by interfering with the N-terminus binding to membranes and chaperone, and provide a molecular basis for the pathological role of C-terminal truncation in PD pathogenesis. C-terminal truncation of a-syn results in a more extended and exposed conformation, providing further insight into the pathological role of this truncation event in the progression of Parkinson's disease.
- Subjects
ALPHA-synuclein; NUCLEAR magnetic resonance spectroscopy; PROTEIN disulfide isomerase; MOLECULAR chaperones; PARKINSON'S disease; CELL aggregation; ASSISTED suicide
- Publication
Communications Biology, 2022, Vol 5, Issue 1, p1
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-022-03768-0