Inhibitors of LRRK2 kinase attenuate neurodegeneration and Parkinson-like phenotypes in C. elegans and Drosophila Parkinson’s disease models

Mutations in LRRK2 have been identified as a genetic cause of familial Parkinson’s disease (PD), and mutations in LRRK2 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 C. 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. at U nirsity of A labam a on July 5, 2011 hm g.oxfournals.org D ow nladed fom