C-terminal truncation modulates α-Synuclein's cytotoxicity and aggregation by promoting the interactions with membrane and chaperone

alpha-Synuclein (alpha-syn) is the main protein component of Lewy bodies, the major pathological hallmarks of Parkinson's disease (PD). C-terminally truncated alpha-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 alpha-syn. Here, we use nuclear magnetic resonance spectroscopy to show that the truncation alters alpha-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 alpha-syn fibrillation. Our findings reveal a modulatory role for the C-terminus in the cytotoxicity and aggregation of alpha-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.

Automated summary

In this study, nuclear magnetic resonance spectroscopy was used to show that C-terminal truncation of alpha-synuclein alters its conformation, resulting in decreased binding of the N-terminus to membranes and molecular chaperones, which affects its cytotoxicity and aggregation. These findings provide insights into the pathological role of C-terminal truncation in Parkinson's disease.