Pharmacology and Chemical Biology Seminar Series

Pharmacology & Chemical Biology Seminar Series
4/22/2021 - 12:00 PM-1:00 PM

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.