QBI and Rezo Therapeutics present Dario Alessi, Director and Principal Investigator for the MRC Protein Phosphorylation and Ubiquitylation Unit at University of Dundee. Dario is a biochemist whose research focuses on unravelling the roles of poorly characterised components which regulate protein phosphorylation or ubiquitylation pathways linked to human disease. He has contributed to our understanding of several disease relevant signal transduction pathways including PDK1 (diabetes and cancer), LKB1 (cancer), WNKs (blood pressure). Much of Dario’s current work is focused on understanding LRRK2 and how mutations in this enzyme cause Parkinson’s disease. Dario Alessi’s publications have accumulated over 95,000 citations (h-index 149). He has obtained several awards including the Francis Crick Medal and Lecture (2006) and election to the UK Royal Society (2008). Dario obtained a BSc (1988) and PhD (1991) from the University of Birmingham and carried out postdoctoral at the University of Dundee from (1991 to 1996).

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. Dario's talk will overview the nuts and bolts of 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. He will discuss a new protein complex that they have identified interacts with the pRAB8A:RILPL1 complex. Dario will consider how mutations in other components linked to Parkinson’s such as Rab29 and VPS35 promote LRRK2 mediated Rab protein phosphorylation as well as characterization of the PPM1H phosphatase member that counteracts LRRK2 signalling by dephosphorylating Rab proteins. He will discuss the implications that this work has for the diagnosis and treatment of Parkinson’s disease.

Talk Title: Interplay between LRRK2 kinase and Rab GTPases in Parkinson’s disease

Host: Natalia Jura