SENP2-based N-terminal truncation of α-synuclein in Lewy pathology propagation

α-Synuclein (αSyn) is a major component of Lewy bodies (LBs) and Lewy neurites (LNs) which are pathological features of Parkinson’s disease (PD) and Dementia with Lewy bodies. In the PD brain, with disease progression, LB/LN formation is propagated from the lower brainstem to the cerebral cortex. Prion-like cell-to-cell seed-transmission has been implicated as an underlying mechanism for Lewy-pathology propagation. However, the biochemical properties and production mechanism of those pathogenic seeds are unelucidated. In this study, we ascertained that the seeds released from pathological neurons that harbour LB/LN-like aggregates have the N-terminally truncated form of αSyn. This N-terminal truncation is directly catalysed by SENP2, which is a well-known deSUMOylation enzyme. After SENP2 processing of recombinant αSyn, the SDS-resistant high-molecular oligomer formation was promoted in vitro . Inhibition of SENP2 activity suppressed aggregate formation and propagation in cultured neurons and mouse brains. Thus, SENP2 might be a novel therapeutic target in LB diseases.