Adamantios Mamais, Jillian H Kluss, Luis Bonet-Ponce, Natalie Landeck, Rebekah G Langston, Nathan Smith, Alexandra Beilina, Alice Kaganovich, Manik C Ghosh, Laura Pellegrini, Ravindran Kumaran, Ioannis Papazoglou, George R Heaton, Rina Bandopadhyay, Nunziata Maio, Changyoun Kim, Matthew J LaVoie, David C Gershlick, Mark R Cookson
Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant Parkinson disease (PD), while polymorphic LRRK2 variants are associated with sporadic PD. PD-linked mutations increase LRRK2 kinase activity and induce neurotoxicity in vitro and in vivo. The small GTPase Rab8a is a LRRK2 kinase substrate and is involved in receptor-mediated recycling and endocytic trafficking of transferrin, but the effect of PD-linked LRRK2 mutations on the function of Rab8a is poorly understood. Here, we show that gain-of-function mutations in LRRK2 induce sequestration of endogenous Rab8a to lysosomes in overexpression cell models, while pharmacological inhibition of LRRK2 kinase activity reverses this phenotype...
December 2021: PLoS Biology