Abstract Glia serve as double-edged swords to modulate neuropathology in Parkinson’s disease (PD), but how they react opposingly to be beneficial or detrimental under pathological conditions, like promote or eliminate α-synuclein (α-syn) inclusions, remains elusive. Here we present evidence that the PD risk factor Cyclin G-associated kinase (GAK)/dAuxilin (dAux) regulates the lysosomal degradation of α-syn in glia. In addition to a broad spectrum of parkinsonian symptoms in Drosophila and mice, lack of glial Gak/dAux causes abnormally higher α-syn levels in fly and mouse brains, and further enhances the α-syn preformed fibril levels in mouse brains. dAux phosphorylates at the serine 543 of Vha44, the V1C subunit of the vacuolar H + -ATPase (V-ATPase), regulates the V-ATPase assembly, and controls the lysosomal acidification and hydrolase activity to set an acidic milieu for α-syn degradation in glia. Importantly, blocking Vha44 serine 543 phosphorylation disrupts V-ATPase assembly, lysosome acidification, and hydrolase activity, leading to DA neurodegeneration and locomotor deficits in flies. Our findings identify a phosphorylation-dependent switch controlling the V-ATPase assembly for lysosomal α-syn degradation in glia. Targeting the clearance of glial α-syn inclusions via this lysosomal pathway could potentially be a therapeutical approach to ameliorate the disease progression in PD.

A phosphorylation-dependent switch of the lysosomal V-ATPase assembly regulates α-synuclein clearance in glia