C-terminal Truncation Modulates α-Synuclein's Cytotoxicity and Aggregation by Promoting the Interactions with Membrane and Chaperone

Overview

Journal Commun Biol

Specialty Biology

Date 2022 Aug 9

PMID 35945337

Authors

Cai Zhang

Yunshan Pei

Zeting Zhang

Lingling Xu

Xiaoli Liu

Ling Jiang

Gary J Pielak

Xin Zhou

Maili Liu

Conggang Li

Affiliations

Soon will be listed here.

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.

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