LRRK2 Interacts with Endosomal Vesicular SNAREs and Regulates Secretion

Abstract

LRRK2 was suggested to regulate endolysosomal dynamics, a process which relies particularly on membrane fusion mediated by SNAREs. Here we investigated the biochemical links between LRRK2 and v-SNAREs and their potential cellular functions. We found that LRRK2 interacted with the post-Golgi v-SNAREs VAMP4, VAMP7 and VAMP8. Parkinson’s disease related R1441C mutant of LRRK2 was the most efficient VAMP4 interactor and lead to impaired VAMP4 subcellular localization. Yeast-2-Hybrid assay identified the interaction of VAMP partner Snapin with the COR domain of LRRK2. LRRK2, Snapin and VAMP4 were found in the same protein complex. Secretomics showed that VAMP4- and VAMP7-KO neuronal cells secreted less pro-VGF, a Parkinson’s disease potential biomarker. R1441C mutant affected the subcellular localization of VGF and LRRK2 expression inhibited the secretion of pro-VGF and delayed Golgi exit of TNFα. Altogether, these results suggest that LRRK2 might regulate secretion of propeptides via interaction with VAMP4 and VAMP7.

Keywords: LRRK2, SNARE, secretomics, Parkinson's disease, VGF, propeptides