Synaptojanin-1 supports VPS35-dependent trafficking of dopamine D2 autoreceptors at presynaptic terminals.

ABSTRACT: Synaptic dysfunction is a hallmark of early Parkinson's disease (PD), but molecular mechanisms underlying dopaminergic synaptic impairment and vulnerability remain poorly understood. Here, we identify a functional interaction between two PD genes, Synaptojanin1 and VPS35, in regulating endosomal sorting of the dopamine D2 short (D2S) autoreceptor, thereby modulating dopamine signaling. We show that Synaptojanin1 deficiency results in intracellular retention of the D2S, impaired gating of dopamine release and reduced behavioral responsiveness to a D2-like agonist. VPS35 is recruited to D2S-containing and Rab7a-positive endosomes in a Synj1-dependent manner, and VPS35 overexpression overcomes Synj1 deficiency-associated impairment in D2S surface delivery in axons. Moreover, Synj1 regulates V

SUBMITTER: Kumar N 

PROVIDER: S-EPMC12633164 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature