Abstract
Activating mutations in LRRK2 kinase causes Parkinson's disease. Pathogenic LRRK2 phosphorylates a subset of Rab GTPases and blocks ciliogenesis. Thus, defining novel phospho-Rab interacting partners is critical to our understanding of the molecular basis of LRRK2 pathogenesis. RILPL2 binds with strong preference to LRRK2-phosphorylated Rab8A and Rab10. RILPL2 is a binding partner of the motor protein and Rab effector, Myosin Va. We show here that the globular tail domain of Myosin Va also contains a high affinity binding site for LRRK2-phosphorylated Rab10. In the presence of pathogenic LRRK2, RILPL2 and MyoVa relocalize to the peri-centriolar region in a phosphoRab10-dependent manner. PhosphoRab10 retains Myosin Va over pericentriolar membranes as determined by fluorescence loss in photobleaching microscopy. Without pathogenic LRRK2, RILPL2 is not essential for ciliogenesis but RILPL2 over-expression blocks ciliogenesis in RPE cells independent of tau tubulin kinase recruitment to the mother centriole. These experiments show that LRRK2 generated-phosphoRab10 dramatically redistributes a significant fraction of Myosin Va and RILPL2 to the mother centriole in a manner that likely interferes with Myosin Va's role in ciliogenesis.
Highlights
Activating mutations in the LRRK2 kinase cause Parkinson’s disease (Alessi & Sammler, 2018)
We show that the Myosin Va (MyoVa) globular tail domain (GTD) contains a high affinity binding site for LRRK2phosphorylated Rab10, and LRRK2 kinase activity and pRab10 drive MyoVa and RILPL2 to the mother centriole during ciliogenesis blockade, retarding the release of MyoVa from that location
We determined the localization of RILPL2 in primary astrocytes that were isolated using antibody immunopanning from brains of newborn rats (Foo et al, 2011)
Summary
Activating mutations in the LRRK2 kinase cause Parkinson’s disease (Alessi & Sammler, 2018). Phosphorylation of Rab proteins blocks their abilities to interact with key regulators including Rab GDI and the Rabin guanine nucleotide exchange factor, as well as multiple, cognate Rab effector proteins (Steger et al, 2016). This loss of effector binding alone would be sufficient to interfere with Rab protein physiological functions. Phosphorylated Rab proteins show enhanced binding to novel effectors, and understanding the roles of these nascent interactions is critical to our understanding of the molecular basis of Parkinson’s disease pathogenesis
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call