C-terminal truncation exacerbates the aggregation and cytotoxicity of α-Synuclein: A vicious cycle in Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disease which usually associates with neuroin-flammation. The main pathological characteristics of PD are dopaminergic neurons death and the presence of Lewy bodies which are composed of aggregated alpha-synuclein (alpha-Syn). Truncated forms of alpha-Syn are found in the brain of PD patients, and account for 10-30% of total synuclein in Lewy bodies. Caspase-1, which plays an important role in neuroinflammation, cleaves full-length alpha-Syn (alpha-Syn FL) to generate a C-terminus 19-residues truncated alpha-Syn (alpha-Syn121). However, the role of truncated alpha-Syn in the onset and/or pathogenesis of PD is unclear. Here, we used alpha-Syn121 as a model to explore its aggregation, membrane disruption and cytotoxicity properties. Compared with alpha-Syn FL, alpha-Syn121 aggregated at an accelerated rate, and formed amorphous aggregates rich in random coil structures rather than beta-sheet-rich linear fibrils formed by alpha-Syn FL. Importantly, higher cytotoxicity with lower membrane disruption capacity was found for alpha-Syn121 aggregates. Furthermore, alpha-Syn121 aggregates could activate the apoptosis signaling pathway and stimulate the caspase-l-mediated cleavage of alpha-Syn FL to generate alpha-Syn121, which as a result leading to increased levels of endogenous alpha-Syn121 and intracellular 5129 phosphorylated alpha-Syn inclusions. Together, our data suggests a hidden vicious cycle in PD that alpha-Syn121 rapidly forms amorphous aggregates, which activate caspase-1 to cleave alpha-Syn FL and generate more alpha-Syn121, and this cycle may contribute to the onset and/or pathogenesis of PD.