Cathepsin L prevents the accumulation of alpha‐synuclein fibrils in the cell

The deposition of α‐synuclein (α‐Syn) fibrils in neuronal cells has been implicated as a causative factor in Parkinson's disease (PD) and dementia with Lewy Bodies (DLB). α‐Syn can be degraded by autophagy, proteasome, and chaperone‐mediated autophagy, and previous studies have suggested the potency of certain cathepsins, lysosomal proteases, for α‐Syn degradation. However, no studies have comprehensively evaluated all cathepsins. Here, we evaluated the efficacy of all 15 cathepsins using a cell model of α‐Syn fibril propagation and found that overexpression of cathepsin L (CTSL) was the most effective in preventing the accumulation of α‐Syn aggregates. CTSL‐mediated degradation of α‐Syn aggregates was dependent on the autophagy machinery, and CTSL itself promoted autophagy flux. Interestingly, CTSL was effective in autophagic degradation of wild‐type (WT) α‐Syn, but not in the case of A53T and E46K missense mutations, which are causative for familial PD. These results suggest that CTSL is a potential therapeutic strategy for sporadic PD pathology in WT α‐Syn.