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

Zhaohui Liu, Shusei Hamamichi, Byoung Dae Lee, Dejun Yang, Arpita Ray, Guy A. Caldwell, Kim A. Caldwell, Ted M Dawson, Wanli Smith, Valina Dawson

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numberddr312
Pages (from-to)3933-3942
Number of pages10
JournalHuman Molecular Genetics
Volume20
Issue number20
DOIs
StatePublished - Oct 2011

Fingerprint

Caenorhabditis elegans
Leucine
Drosophila
Parkinson Disease
Phosphotransferases
Phenotype
Small Molecule Libraries
Mutation

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Inhibitors of LRRK2 kinase attenuate neurodegeneration and Parkinson-like phenotypes in Caenorhabditis elegans and Drosophila Parkinson's disease models. / Liu, Zhaohui; Hamamichi, Shusei; Lee, Byoung Dae; Yang, Dejun; Ray, Arpita; Caldwell, Guy A.; Caldwell, Kim A.; Dawson, Ted M; Smith, Wanli; Dawson, Valina.

In: Human Molecular Genetics, Vol. 20, No. 20, ddr312, 10.2011, p. 3933-3942.

Research output: Contribution to journalArticle

Liu, Zhaohui ; Hamamichi, Shusei ; Lee, Byoung Dae ; Yang, Dejun ; Ray, Arpita ; Caldwell, Guy A. ; Caldwell, Kim A. ; Dawson, Ted M ; Smith, Wanli ; Dawson, Valina. / Inhibitors of LRRK2 kinase attenuate neurodegeneration and Parkinson-like phenotypes in Caenorhabditis elegans and Drosophila Parkinson's disease models. In: Human Molecular Genetics. 2011 ; Vol. 20, No. 20. pp. 3933-3942.
@article{5b7b4a345cd34bd9adb53947b745dbf0,
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.",
author = "Zhaohui Liu and Shusei Hamamichi and Lee, {Byoung Dae} and Dejun Yang and Arpita Ray and Caldwell, {Guy A.} and Caldwell, {Kim A.} and Dawson, {Ted M} and Wanli Smith and Valina Dawson",
year = "2011",
month = "10",
doi = "10.1093/hmg/ddr312",
language = "English (US)",
volume = "20",
pages = "3933--3942",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "20",

}

TY - JOUR

T1 - Inhibitors of LRRK2 kinase attenuate neurodegeneration and Parkinson-like phenotypes in Caenorhabditis elegans and Drosophila Parkinson's disease models

AU - Liu, Zhaohui

AU - Hamamichi, Shusei

AU - Lee, Byoung Dae

AU - Yang, Dejun

AU - Ray, Arpita

AU - Caldwell, Guy A.

AU - Caldwell, Kim A.

AU - Dawson, Ted M

AU - Smith, Wanli

AU - Dawson, Valina

PY - 2011/10

Y1 - 2011/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=80053152848&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80053152848&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddr312

DO - 10.1093/hmg/ddr312

M3 - Article

C2 - 21768216

AN - SCOPUS:80053152848

VL - 20

SP - 3933

EP - 3942

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 20

M1 - ddr312

ER -