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MAR 11, 2020 7:30 AM PDT

Keynote Presentation: Interplay between LRRK2 protein kinase and Rab GTPases in Parkinson's disease

Presented at: Neuroscience 2020
C.E. Credits: P.A.C.E. CE Florida CE
Speaker
  • Director, Professor of Signal Transduction, University of Dundee
    Biography
      Dario's research focuses on unravelling the roles of poorly characterised components which regulate protein phosphorylation or ubiquitylation pathways that are linked to human disease. Dario, obtained a BSc (1988) and PhD (1991) from the University of Birmingham, United Kingdom. He carried out postdoctoral at the University of Dundee from (1991 to 1997), where he became fascinated by protein kinases and how they are regulated by insulin, growth factors and other extracellular signals that control almost all aspects of cell biology. In 1997 Dario became a program leader in the MRC Protein Phosphorylation Unit, where he was appointed as its Director in 2012. Dario 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's work has contributed to approaches (LRRK2 kinase assay, LRRK2 Ser935 dephosphorylation assay, Rab phosphorylation assays) that have facilitated the development of inhibitors against LRRK2 that may be useful for the treatment of Parkinson's disease. Dario's lab contributed to the discovery and validation of the first physiological substrates for the Parkinson's disease LRRK2 protein kinase to be identified showing that LRRK2 directly phosphorylates a subset of the Rab GTPases on a residue lying within the middle of the effector interacting-switch II domain. Dario in collaboration with the Michael J Fox Foundation to better interrogate and understand LRRK2 biology and how it is impacted by mutations, environment and inhibitors that are being developed and assessed. Dario also serves as the Director of the Dundee Signal Transduction Therapy Unit. This is a unique collaboration between scientists at the University of Dundee and pharmaceutical companies, dedicated to accelerating the development of specific inhibitors and chemical probes that target the protein phosphorylation and ubiquitylation system for the treatment of disease, as well as for the study of cell signalling. Dario has published around 260 papers and has a h-index of 131. To peruse Dario's publications see https://scholar.google.co.uk/citations?user=9gPyVfsAAAAJ&hl=en

    Abstract

    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 discuss 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.  I will discuss 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.

    Learning Objectives:

    1. Define the nuts and bolts of the LRRK2 signaling pathway and how it is linked to Parkinson's disease

    2. Showcases new approaches that could be exploited to better diagnose and Parkinson's disease


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