Targeting two-pore channels in LRRK2-dependent Parkinson Disease

Abstract

Although one of the most common and penetrant genetic risk factors for Parkinson Disease is mutation of the LRRK2 gene, the function of the LRRK2 protein is not entirely clear. Its multi-domain structure conferring protein-protein interactivity and enzymatic function suggests a complex mode of action. Yet potentially druggable signalling pathways downstream of LRRK2 are ill-defined. At the sub-cellular level, LRRK2 localises, at least in part, to lysosomes and regulates traffic events. Such findings add to evidence pointing to defective lysosomes as drivers of PD pathology, and a growing body of literature implicates lysosomal dysfunction in PD. LRRK2 interacts with Rab5 to regulate endocytosis, and with Rab7 to govern lysosomal morphology and lysosomal distribution, the both regulating patho-physiologically important trafficking events within the endolysosomal system. The two-pore channels (TPC1 and TPC2) are novel endo-lysosomal ion channels of contemporary significance following their identification by Patel and others as the long-sought target channels for the Ca2+-mobilising messenger NAADP. It is established that NAADP mediates local Ca2+ signals from acidic organelles which are amplified during signalling by neurotransmitters. Less explored, is whether these local signals may act in their own right to drive "constitutive" fusogenic events within the endolysosomal system to regulate trafficking. But the view that NAADP targets TPCs has been subject to challenge with data suggesting that PI(3,5)P2 is the endogenous ligand. It is notable that PI(3,5)P2 is an endo-lysosomal-specific phosphoinositide and established regulator of trafficking. Such co-regulation by a Ca2+ mobilising second messenger and trafficking lipid renders TPCs as prime candidates in the control of endo-lysosomal trafficking. Moreover, both TPC2 and pathogenic LRRK2 have been very recently implicated in growth factor receptor trafficking. Patel has identified a pronounced lysosome morphology defect in LRRK2-PD patient fibroblasts. Based on these data, we will combine our expertise in TPCs and Parkinson's to test the central hypothesis that LRRK2-mediated dopaminergic dysfunction in Parkinson's can be reversed by inhibiting the lysosomal ion channel TPC2. We will test this using the cellular human dopaminergic neurons and emerging drugs targeting TPC2 as a step towards novel therapies for Parkinson's. (AU)