Pharmacology & Chemical Biology Seminar Series
4/22/2021 - 12:00 PM-1:00 PM
"Interplay between LRRK2 protein kinase and Rab GTPases in Parkinson’s disease"

Dario Alessi, Ph.D.
Director of MRC Protein Phosphorylation and Ubiquitylation Unit
University of Dundee


Autosomal dominant missense mutations that hyperactivate the LRRK2 protein kinase are a common cause of inherited Parkinson’s disease and therapeutic efficacy of LRRK2 inhibitors is being tested in clinical trials. In my presentation I will we overview the nuts and bolts of our current research that has revealed that LRRK2 phosphorylates a subset of Rab GTPases within their Switch-II motif controlling interaction with a new set of effectors such as RILPL1/2 and JIP3/JIP4.  I will present data showing how LRRK2 pathway activity in humans can be interrogated by assessing LRRK2 mediated phosphorylation of Rab10 in neutrophils. I will consider how mutations in other components linked to Parkinson’s such as Rab29 and VPS35 activate LRRK2 and promote Rab protein phosphorylation. I will discuss the identification and characterization of a novel PPM family phosphatase member that counteracts LRRK2 signalling by dephosphorylating Rab proteins. I will present data that indicates that the LRRK2 parlog termed LRRK1 also functions as a Rab kinase.  Finally, I will discuss what is known about how LRRK2 regulates ciliogenesis, the endosomal-lysosome system, and immune responses and how this might be linked to Parkinson’s disease. 

Melanie Hoffner
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