The development of inhibitors of leucine-rich repeat kinase 2 (LRRK2) as a therapeutic strategy for Parkinson's disease: the current state of play.

Current therapeutic approaches for Parkinson's disease (PD) are based around treatments that alleviate symptoms but do not slow or prevent disease progression. As such, alternative strategies are needed. A promising approach is the use of molecules that reduce the function of leucine-rich repeat kinase (LRRK2). Gain-of-function mutations in LRRK2 account for a notable proportion of familial Parkinson's disease cases, and significantly, elevated LRRK2 kinase activity is reported in idiopathic Parkinson's disease. Here, we describe progress in finding therapeutically effective LRRK2 inhibitors, summarising studies that range from in vitro experiments to clinical trials. LRRK2 is a complex protein with two enzymatic activities and a myriad of functions. This creates opportunities for a rich variety of strategies and also increases the risk of unintended consequences. We comment on the strength and limitations of the different approaches and conclude that with two molecules under clinical trial and a diversity of alternative options in the pipeline, there is cause for optimism. LINKED ARTICLES: This article is part of a themed issue on Building Bridges in Neuropharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.8/issuetoc.

LRRK2 Biology from structure to dysfunction: research progresses, but the themes remain the same.

Since the discovery of leucine-rich repeat kinase 2 (LRRK2) as a protein that is likely central to the aetiology of Parkinson's disease, a considerable amount of work has gone into uncovering its basic cellular function. This effort has led to the implication of LRRK2 in a bewildering range of cell biological processes and pathways, and probable roles in a number of seemingly unrelated medical conditions. In this review we summarise current knowledge of the basic biochemistry and cellular function of LRRK2. Topics covered include the identification of phosphorylation substrates of LRRK2 kinase activity, in particular Rab proteins, and advances in understanding the activation of LRRK2 kinase activity via dimerisation and association with membranes, especially via interaction with Rab29. We also discuss biochemical studies that shed light on the complex LRRK2 GTPase activity, evidence of roles for LRRK2 in a range of cell signalling pathways that are likely cell type specific, and studies linking LRRK2 to the cell biology of organelles. The latter includes the involvement of LRRK2 in autophagy, endocytosis, and processes at the trans-Golgi network, the endoplasmic reticulum and also key microtubule-based cellular structures. We further propose a mechanism linking LRRK2 dimerisation, GTPase function and membrane recruitment with LRRK2 kinase activation by Rab29. Together these data paint a picture of a research field that in many ways is moving forward with great momentum, but in other ways has not changed fundamentally. Many key advances have been made, but very often they seem to lead back to the same places.