Inhibitors of LRRK2 kinase attenuate neurodegeneration and Parkinson-like phenotypes in Caenorhabditis elegans and Drosophila Parkinson's disease models

Hum Mol Genet. 2011 Oct 15;20(20):3933-42. doi: 10.1093/hmg/ddr312. Epub 2011 Jul 18.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Benzenesulfonates / pharmacology
  • Caenorhabditis elegans / drug effects
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Disease Models, Animal
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism
  • Drosophila / drug effects
  • Drosophila / genetics
  • Drosophila / metabolism
  • Enzyme Activation / drug effects
  • Enzyme Activation / genetics
  • Humans
  • Indoles / pharmacology
  • Motor Activity / drug effects
  • Motor Activity / genetics
  • Mutation / genetics
  • Niacinamide / analogs & derivatives
  • Oxidopamine / adverse effects
  • Parkinson Disease / enzymology*
  • Parkinson Disease / genetics
  • Parkinson Disease / prevention & control
  • Phenols / pharmacology
  • Phenotype*
  • Phenylurea Compounds
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / genetics
  • Pyridines / pharmacology
  • Sorafenib
  • Synucleins / adverse effects

Substances

  • Benzenesulfonates
  • Indoles
  • Phenols
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Pyridines
  • Synucleins
  • Niacinamide
  • Oxidopamine
  • Sorafenib
  • Protein Serine-Threonine Kinases
  • 5-iodo-3-((3,5-dibromo-4-hydroxyphenyl)methylene)-2-indolinone