Characterisation of the LRRK2 protein kinase, mutated in inherited Parkinson s disease

Parkinson?s disease is a serious degenerative brain disorder resulting in tremors and abnormally slow movements in patients. The disease has no cure and is a major cause of disability and early death worldwide. A recent breakthrough has lead to the discovery that mutations in a gene called LRRK2 can cause Parkinson?s disease in humans. The LRRK2 gene encodes for an enzyme. It is not known how the LRRK2 enzyme works in human brains and how its mutation causes Parkinson?s disease. The purpose of this application is to undertake studies that define how LRRK2 works in the brain. We also aim to learn how mutations in LRRK2 might cause Parkinson?s disease. Moreover, this research will provide knowledge and methodology to facilitate the development of new drugs that target the LRRK2 enzyme for the treatment of Parkinson?s disease ? and possibly dementias such as Alzheimer?s disease.

There has been much interest raised by the recent discovery that different autosomal dominant point mutations within the gene encoding for the Leucine Rich Repeat protein Kinase-2 (LRRK2), predispose humans to develop late-onset Parkinson?s disease (PD), with a clinical appearance indistinguishable from idiopathic PD. Mutations in LRRK2 are relatively frequent, accounting for 5-10% of familial PD, and are also found in a significant proportion of sporadic PD cases. Little is known about how LRRK2 is regulated in cells, what are its physiological substrates and how mutations in LRRK2 cause or increase risk of PD. The most prevalent mutant form of LRRK2 comprises an amino acid substitution of Gly2019 within the kinase domain that enhances the kinase activity of LRRK2 three-fold. The purpose of this application would be to build upon ongoing LRRK2-based research within the MRC Protein Phosphorylation Unit and GlaxoSmithKline. We will focus on studying the expression, activity and function of endogenous LRRK2 protein, especially in primary neuronal cells and tissues. We would study which agonists and upstream signalling pathways control LRRK2 activity and undertake experiments to assess the role of LRRK2 in phosphorylating moesin and related proteins that we have recently discovered to be efficiently phosphorylated by LRRK2 in vitro. Overall the aim of this research is to better define the cellular roles of LRRK2 and obtain insight into how LRRK2 mutations might contribute to Parkinson?s disease and other Neurodegenerative diseases, including Alzheimer?s disease. This work would effectively utilise the strengths to be gained through academic/industrial collaboration to cement and rapidly exploit an area of new scientific breakthrough in relation to neurodegenerative diseases. It would also provide the pharmaceutical industry with better knowledge and reagents to prosecute LRRK2 as a drug target and to test the efficacy and selectivity of drugs developed against this enzyme.