3.5 year MRC PhD iCASE Project: Mechanism by which VPS35 controls activity of the LRRK2 Parkinson’s disease kinase

There is great need for improved understanding of the mechanistic biology underlying Parkinson’s as well as the development of new drugs that slow the progression of the disease. The discovery that hyperactivating mutations in a protein kinase termed LRRK2 causes Parkinson’s, offers the prospect of elaborating new, potentially disease-modifying treatments in at least a subset of patients. The applicants (Alessi-Dundee and Reith-GlaxoSmithKline) have had a major collaboration to better understand LRRK2 over the last 10 years, that has resulted in several joint publications including discovery that the physiological substrates of LRRK2 comprise a subgroup of Rab GTPases proteins (Ref-1). Recent advances point towards LRRK2 controlling autophagy and lysosome function by phosphorylating these Rab proteins and regulating their ability to bind cognate effector proteins. In recent studies we have started to explore whether mutations in other genes linked to heritable forms of Parkinson’s activate LRRK2 (Ref-2). This work has resulted in the discovery that a ddisease-causing mutation in VPS35 (D620N) that encodes for a component of the retromer complex that regulates trafficking of cargo from endosomes (Ref-3), strikingly controls LRRK2 (unpublished). Moreover, knock-out or knockdown of VPS35 also markedly impacts LRRK2 in cells. The goal of the student appointed to this project would be to dissect the detailed molecular mechanism by which VPS35 regulates LRRK2. This would include generating tools to better study VPS35 as well discovering and characterising the key regulator(s) linking VPS35 and LRRK2 in disease. This studentship provides a fantastic opportunity for a talented student to gain valuable experience in working at the forefront of an important area of Parkinson’s. This project will provide training expertise in the state of the art biochemistry, molecular biology, cell signalling, mass spectrometry, data analysis as well as generic (statistics, communication, written and oral presentation). It is expected that the student would work for a 3-4-month period in GlaxoSmithKline thereby gaining valuable experience of working in a pharmaceutical company.