Synergistic effect of mutations in the Parkinson’s disease-linked endocytic proteins synaptojanin 1 (PARK20) and auxilin (PARK19)

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by defective dopaminergic (DAergic) input to the striatum. Mutations in two genes encoding synaptically-enriched clathrin-uncoating factors, synaptojanin 1 (SJ1) and auxilin, have been implicated in PD. SJ1 knock-in (SJ1-KI^RQ) mice carrying PD mutation display neurological manifestation reminiscent of PD. Here we report that auxilin knockout (Aux-KO) mice display dystrophic changes of a subset of nigrostriatal DAergic terminals similar to those of SJ1-KI^RQ mice. Furthermore, Aux-KO/SJ1-KI^RQ double mutant mice have shorter lifespan and more severe synaptic defects than single mutant mice. These include increase in dystrophic striatal nerve terminals positive for DAergic markers and for the PD risk protein SV2C, as well as adaptive changes in striatal interneurons. The synergistic effect of the two mutations demonstrates a special lability of DAergic neurons to defects in clathrin uncoating, with implications for PD pathogenesis in at least some forms of this condition.