Abstractα-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.

α-synuclein (α-syn) is the main protein component of Lewy bodies, the major pathological hallmarks of Parkinson’s disease (PD). C-terminal truncated forms of α-syn are found in the brain of PD patients, and reduce cell viability, as well as tend to form fibrils. Nevertheless, little is known about the molecular mechanisms underlying the role of C-terminal truncation on the cytotoxicity and aggregation of α-syn. The N-terminal domain of α-syn interacts with membranes and molecular chaperones, and these interactions are critical for the protein’s physiological function and its pathological effects in PD. Here, we use nuclear magnetic resonance spectroscopy, a co-flotation assay, dynamic light scattering, and thioflavin T fluorescence to show that the truncation alters α-syn conformation, resulting in a new attractive interaction of the N-terminus with membranes and molecular chaperone, protein disulfide isomerase (PDI). Remarkably, 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 the interaction of the N-terminus with membrane and chaperone.

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