VPS35 Interacts with Dopamine Transportor and Disrupts Dopamine Transporter Recycling Pathway

The exact pathophysiological role of vacuolar protein sorting 35 ortholog (VPS35) in Parkinson's disease (PD) is unknown. Here, we have identified dopaminergic transportor (DAT) as an interacting partner of VPS35. Mutant VPS35 D620N and DAT interaction causes a decrease in membrane DAT by disrupting DAT transport from an early endosome to a recycling endosome via weaker binding to FAM21. The in vitro interactions are further validated in the VPS35-D620N transgenic C. elegans and mice with the AAV-mediated overexpression of VPS35-D620N, which displayed key features of human PD. Our findings identified a novel pathway linking endosomal recycling as a mechanistic link with VPS35 associated PD that could potentially unravel new therapeutic targets. Funding Statement: The study was partly supported by the grants from: the National Natural Science Foundation of China (No. 81671102, 81873751 ); the National Key Research and Development Program of China, Stem Cell and Translational Research (No. 2017YFA0105104); Guangdong provincial science and technology plan project (No. 2016B030230002, 2017A040406007); Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases; The Southern China International Cooperation Base for Early Intervention and Functional Rehabilitation of Neurological Diseases (2015B050501003); Guangdong Provincial engineering Center for Major Neurological Disease Treatment. Declaration of Interests: The authors declare no competing financial interests. Ethics Approval Statement: Mice were maintained in accordance with institutional guidelines, and all protocols were approved by the Institutional Animal Care and Use Committee (IACUC) of the First Affiliated Hospital, Sun Yat-sen University, China.