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Article Dans Une Revue Cell Reports Année : 2023

Secretion of VGF relies on the interplay between LRRK2 and post-Golgi v-SNAREs

Stéphanie Blanchon
  • Fonction : Auteur
Jean-Christophe Rain
Chiara Guerrera

Résumé

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
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Dates et versions

hal-04090504 , version 1 (05-05-2023)

Identifiants

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Francesca Filippini, Sébastien Nola, Ahmed Zahraoui, Kevin Roger, Mansoore Esmaili, et al.. Secretion of VGF relies on the interplay between LRRK2 and post-Golgi v-SNAREs. Cell Reports, 2023, 42 (3), pp.112221. ⟨10.1016/j.celrep.2023.112221⟩. ⟨hal-04090504⟩
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