Secretion of VGF relies on the interplay between LRRK2 and post-Golgi v-SNAREs
Francesca Filippini,
Sébastien Nola,
Ahmed Zahraoui,
Kevin Roger,
Mansoore Esmaili,
Ji Sun,
José Wojnacki,
Anaïs Vlieghe,
Philippe Bun,
Stéphanie Blanchon,
Jean-Christophe Rain,
Jean-Marc Taymans,
Marie-Christine Chartier-Harlin,
Chiara Guerrera,
Thierry Galli
Affiliations
Francesca Filippini
Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, INSERM U1266, Membrane Traffic in Healthy & Diseased Brain, 75014 Paris, France
Sébastien Nola
Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, INSERM U1266, Membrane Traffic in Healthy & Diseased Brain, 75014 Paris, France
Ahmed Zahraoui
Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, INSERM U1266, Membrane Traffic in Healthy & Diseased Brain, 75014 Paris, France
Kevin Roger
Université Paris Cité, Proteomics Platform Necker, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS3633, 75015 Paris, France
Mansoore Esmaili
Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Ji Sun
Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
José Wojnacki
Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, INSERM U1266, Membrane Traffic in Healthy & Diseased Brain, 75014 Paris, France
Anaïs Vlieghe
Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, INSERM U1266, Membrane Traffic in Healthy & Diseased Brain, 75014 Paris, France
Philippe Bun
Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, NeurImag Imaging Facility, 75014 Paris, France
Stéphanie Blanchon
Hybrigenics Services, 91000 Évry-Courcouronnes, France
Jean-Christophe Rain
Hybrigenics Services, 91000 Évry-Courcouronnes, France
Jean-Marc Taymans
Université de Lille, INSERM, CHU Lille, UMR-S1172, LilNCog – Lille Neuroscience & Cognition, Lille, France
Marie-Christine Chartier-Harlin
Université de Lille, INSERM, CHU Lille, UMR-S1172, LilNCog – Lille Neuroscience & Cognition, Lille, France
Chiara Guerrera
Université Paris Cité, Proteomics Platform Necker, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS3633, 75015 Paris, France
Thierry Galli
Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, INSERM U1266, Membrane Traffic in Healthy & Diseased Brain, 75014 Paris, France; GHU Paris Psychiatrie & Neurosciences, Paris, France; Corresponding author
Summary: The neuropeptide VGF was recently proposed as a neurodegeneration biomarker. The Parkinson’s disease-related protein leucine-rich repeat kinase 2 (LRRK2) regulates endolysosomal dynamics, a process that involves SNARE-mediated membrane fusion and could regulate secretion. Here we investigate potential biochemical and functional links between LRRK2 and v-SNAREs. We find that LRRK2 directly interacts with the v-SNAREs VAMP4 and VAMP7. Secretomics reveals VGF secretory defects in VAMP4 and VAMP7 knockout (KO) neuronal cells. In contrast, VAMP2 KO “regulated secretion-null” and ATG5 KO “autophagy-null” cells release more VGF. VGF is partially associated with extracellular vesicles and LAMP1+ endolysosomes. LRRK2 expression increases VGF perinuclear localization and impairs its secretion. Retention using selective hooks (RUSH) assays show that a pool of VGF traffics through VAMP4+ and VAMP7+ compartments, and LRRK2 expression delays its transport to the cell periphery. Overexpression of LRRK2 or VAMP7-longin domain impairs VGF peripheral localization in primary cultured neurons. Altogether, our results suggest that LRRK2 might regulate VGF secretion via interaction with VAMP4 and VAMP7.
