title: Is inhibition of kinase activity the only therapeutic strategy for LRRK2-associated Parkinson's disease?
abstract: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a common cause of familial Parkinson's disease (PD). Variation around the LRRK2 locus also contributes to the risk of sporadic PD. The LRRK2 protein contains a central catalytic region, and pathogenic mutations cluster in the Ras of complex protein C terminus of Ras of complex protein (mutations N1437H, R1441G/C and Y1699C) and kinase (G2019S and I2020T) domains. Much attention has been focused on the kinase domain, because kinase-dead versions of mutant LRRK2 are less toxic than kinase-active versions of the same proteins. Furthermore, kinase inhibitors may be able to mimic this effect in mouse models, although the currently tested inhibitors are not completely specific. In this review, we discuss the recent progress in the development of specific LRRK2 kinase inhibitors. We also discuss non-kinase-based therapeutic strategies for LRRK2-associated PD as it is possible that different approaches may be needed for different mutations.
authors.affiliation: Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, 35 Convent Drive, Room 1A-116, Bethesda, MD 20892-3707, USA.
authors.forename: Iakov N
authors.initials: IN
authors.lastname: Rudenko
authors.forename: Ruth
authors.initials: R
authors.lastname: Chia
authors.forename: Mark R
authors.initials: MR
authors.lastname: Cookson
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D006801:Humans; D009154:Mutation / Q000235:genetics; D010300:Parkinson Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D057170:Translational Research, Biomedical
chemical_list: D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases