Disarming CH25H to clear α-synuclein.

α-Synuclein (α-Syn) accumulation is a defining feature of Parkinson's disease (PD). Zhang et al. identify cholesterol 25-hydroxylase (CH25H) as an astrocytic inhibitor of p62-dependent α-Syn degradation. Disrupting the CH25H-p62 interaction facilitates α-Syn clearance via autophagy and improves PD-like phenotypes, suggesting a previously unrecognized nonenzymatic function for CH25H with therapeutic potential.