Parkinson's disease predisposing LRRK2 kinase phosphorylates a group of Rab GTPase proteins including Rab29, within the effector‐binding switch II motif. Previous work indicated that Rab29, located within the PARK16 locus mutated in Parkinson's patients, operates in a common pathway with LRRK2. Here, we show that Rab29 recruits LRRK2 to the trans‐Golgi network and greatly stimulates its kinase activity. Pathogenic LRRK2 R1441G/C and Y1699C mutants that promote GTP binding are more readily recruited to the Golgi and activated by Rab29 than wild‐type LRRK2. We identify conserved residues within the LRRK2 ankyrin domain that are required for Rab29‐mediated Golgi recruitment and kinase activation. Consistent with these findings, knockout of Rab29 in A549 cells reduces endogenous LRRK2‐mediated phosphorylation of Rab10. We show that mutations that prevent LRRK2 from interacting with either Rab29 or GTP strikingly inhibit phosphorylation of a cluster of highly studied biomarker phosphorylation sites (Ser910, Ser935, Ser955 and Ser973). Our data reveal that Rab29 is a master regulator of LRRK2, controlling its activation, localization, and potentially biomarker phosphorylation.
Zimprich, A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M., Lincoln, S., Kachergus, J., Hulihan, M., Uitti, R.J., Calne, D.B., Stoessl, A. J., Pfeiffer, R. F., Patenge, N., Carbajal, I. C., Vieregge, P., Asmus, F., Muller‐Myhsok, B., Dickson, D. W., Meitinger, T., Strom, T. M. et al (2004) Mutations in LRRK2 cause autosomal‐dominant parkinsonism with pleomorphic pathology. Neuron 44: 601–607
Fukuda, M. (2016) Multiple roles of VARP in endosomal trafficking: Rabs, Retromer components and R‐SNARE VAMP7 meet on VARP. Traffic 17: 709–719
Al-Jarrah, M. D., & Erekat, N. S. (2017). Parkinson disease-induced upregulation of apoptotic mediators could be attenuated in the skeletal muscle following chronic exercise training. NeuroRehabilitation, 41(4), 823-830.
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