Although most cases of PD are of largely unknown cause (idiopathic PD), the discovery of rare genetic forms has provided great insight into key cellular processes which are at the root of the disease and have led to the development of new treatments that are now entering clinical trials. One of the most exciting examples are drugs that block the ‘faulty LRRK2 gene’ called ‘LRRK2 kinase inhibitors’. While genetic changes in LRRK2 directly cause 1-2% of all PD cases, data is emerging that LRRK2 could also be a driver in the more common idiopathic form. Interestingly, genetic variants in LRRK2 have also been associated with other diseases, including Crohn’s disease. A project is available to interrogate the LRRK2 kinase pathway in human bio-samples of individuals with familial / monogenetic Parkinson’s disease as well as other conditions to identify those with LRRK2 kinase hyperactivation. The particular disease-associated mutation or top genetic variants identified in those patients with LRRK2 kinase hyperactivation will then be further characterized using cell based and in vitro approaches to establish the underlying molecular mechanism. The project will use state-of-the-art biochemistry, proteomics and utilize unique and ongoing collections of human bio-samples. The expectation is that this project will provide us with insight into the LRRK2 signalling network and regulation therefore in human diseases and assist in the development integrated (clinical, genetic and mechanistic) stratification methods to match patients with the most appropriate clinical trial or emerging therapy.
The Parkinson’s disease VPS35[D620N] mutation enhances LRRK2 mediated Rab protein phosphorylation in mouse and human Mir, M#; Tonelli F#; Lis, P; Macartney, T; Polinski, NK; Martinez, TN; Chou, M; Howden, AJM, König, T; Hotzy, C; Milenkovic, I; Brücke, T; Zimprich, A; Sammler, E*& Alessi, DR* (*joint corresponding authors) Biochem J. 2018 Jun 6;475(11):1861-1883. doi: 10.1042/BCJ20180248.
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Interrogating Parkinson’s disease LRRK2 kinase pathway activity by assessing Rab10 phosphorylation in human neutrophils. Fan, Y., Howden, A., Sarhan, A.R., Lis, P., Ito, G., Martinez, T.N., Brockmann, K., Gasser, T., Alessi D.R. & Sammler, E. Biochem J. 2018 Jan 2;475(1):23-44. doi: 10.1042/BCJ20170803.