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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 VPS35 expression and localization in dopaminergic axons, indicating their broader roles in presynaptic cargo sorting. These findings reveal a novel cooperation between a synaptic vesicle endocytic regulator and a core component of the retromer complex, providing new mechanistic insights into presynaptic trafficking and its disruption in PD.
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