title: Inhibitors of LRRK2 kinase attenuate neurodegeneration and Parkinson-like phenotypes in Caenorhabditis elegans and Drosophila Parkinson's disease models.
abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2) have been identified as a genetic cause of familial Parkinson's disease (PD) and have also been found in the more common sporadic form of PD, thus positioning LRRK2 as important in the pathogenesis of PD. Biochemical studies of the disease-causing mutants of LRRK2 implicates an enhancement of kinase activity as the basis of neuronal toxicity and thus possibly the pathogenesis of PD due to LRRK2 mutations. Previously, a chemical library screen identified inhibitors of LRRK2 kinase activity. Here, two of these inhibitors, GW5074 and sorafenib, are shown to protect against G2019S LRRK2-induced neurodegeneration in vivo in Caenorhabditis elegans and in Drosophila. These findings indicate that increased kinase activity of LRRK2 is neurotoxic and that inhibition of LRRK2 activity can have a disease-modifying effect. This suggests that inhibition of LRRK2 holds promise as a treatment for PD.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Liu
authors.forename: Shusei
authors.initials: S
authors.lastname: Hamamichi
authors.forename: Byoung Dae
authors.initials: BD
authors.lastname: Lee
authors.forename: Dejun
authors.initials: D
authors.lastname: Yang
authors.forename: Arpita
authors.initials: A
authors.lastname: Ray
authors.forename: Guy A
authors.initials: GA
authors.lastname: Caldwell
authors.forename: Kim A
authors.initials: KA
authors.lastname: Caldwell
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
authors.forename: Wanli W
authors.initials: WW
authors.lastname: Smith
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001557:Benzenesulfonates / Q000494:pharmacology; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D004330:Drosophila / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009536:Niacinamide / Q000031:analogs & derivatives; D016627:Oxidopamine / Q000009:adverse effects; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D010636:Phenols / Q000494:pharmacology; D010641:Phenotype; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D000077157:Sorafenib; D051843:Synucleins / Q000009:adverse effects
chemical_list: D001557:Benzenesulfonates; D007211:Indoles; D010636:Phenols; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D051843:Synucleins; D009536:Niacinamide; D016627:Oxidopamine; D000077157:Sorafenib; D017346:Protein Serine-Threonine Kinases; C489251:5-iodo-3-((3,5-dibromo-4-hydroxyphenyl)methylene)-2-indolinone