Cholestanol accelerates α-synuclein aggregation and spreading by activating asparagine endopeptidase

Cerebrotendinous xanthomatosis (CTX), an autosomal recessive disorder characterized by high levels of cholestanol in the blood and accumulation of cholestanol in multiple tissues, especially the brain, often presents in parkinsonism. However, it remains unknown whether cholestanol plays a role in the pathogenesis of sporadic Parkinson's disease (PD). Here, we show that the levels of serum cholestanol in patients with sporadic PD are higher than those in control participants. Cholestanol activates the protease asparagine endopeptidase (AEP) and induces the fragmentation of alpha-synuclein (alpha-syn) and facilitates its aggregation. Furthermore, cholestanol promotes the spreading of alpha-syn pathology in a mouse model induced by intrastriatal injection of alpha-syn fibrils. KO of AEP or administration of an AEP inhibitor ameliorates alpha-syn pathology, degeneration of the nigrostriatal dopaminergic pathway, and PD-like motor symptoms. These results not only indicate that cholestanol contributes to the aggregation and spreading of alpha-syn by activating AEP but also reveal an opportunity for treating PD with AEP inhibitors.