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PMID: 19625511 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

LRRK2 modulates vulnerability to mitochondrial dysfunction in Caenorhabditis elegans.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 29 ·No. 29 ·2009-07-22 ·Pages 9210-8

Saha S, Guillily MD, Ferree A, Lanceta J, Chan D, Ghosh J, Hsu CH, Segal L, Raghavan K, Matsumoto K, Hisamoto N, Kuwahara T, Iwatsubo T, Moore L, Goldstein L, Cookson M, Wolozin B

Abstract

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal-dominant familial Parkinson's disease. We generated lines of Caenorhabditis elegans expressing neuronally directed human LRRK2. Expressing human LRRK2 increased nematode survival in response to rotenone or paraquat, which are agents that cause mitochondrial dysfunction. Protection by G2019S, R1441C, or kinase-dead LRRK2 was less than protection by wild-type LRRK2. Knockdown of lrk-1, the endogenous ortholog of LRRK2 in C. elegans, reduced survival associated with mitochondrial dysfunction. C. elegans expressing LRRK2 showed rapid loss of dopaminergic markers (DAT::GFP fluorescence and dopamine levels) beginning in early adulthood. Loss of dopaminergic markers was greater for the G2019S LRRK2 line than for the wild-type line. Rotenone treatment induced a larger loss of dopamine markers in C. elegans expressing G2019S LRRK2 than in C. elegans expressing wild-type LRRK2; however, loss of dopaminergic markers in the G2019S LRRK2 nematode lines was not statistically different from that in the control line. These data suggest that LRRK2 plays an important role in modulating the response to mitochondrial inhibition and raises the possibility that mutations in LRRK2 selectively enhance the vulnerability of dopaminergic neurons to a stressor associated with Parkinson's disease.

MeSH Terms
Aging Animals Animals, Genetically Modified Caenorhabditis elegans Dopamine/metabolism Gene Knockdown Techniques Herbicides/toxicity Insecticides/toxicity Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Mitochondria/drug effects,physiology Mortality Mutation Neurons/drug effects,physiology Paraquat/toxicity Protein Serine-Threonine Kinases/genetics,metabolism RNA, Messenger/metabolism Rotenone/toxicity
Chemicals
Herbicides Insecticides RNA, Messenger Rotenone LRK-1 protein, C elegans LRRK2 protein, human Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Protein Serine-Threonine Kinases Paraquat Dopamine
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Saha Shamol
Department of Pharmacology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Guillily Maria D
Ferree Andrew
Lanceta Joel
Chan Diane
Ghosh Joy
Hsu Cindy H
Segal Lilach
Raghavan Kesav
Matsumoto Kunihiro
Hisamoto Naoki
Kuwahara Tomoki
Iwatsubo Takeshi
Moore Landon
Goldstein Lee
Cookson Mark
Wolozin Benjamin
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.2281-09.2009
Published
2009-07-22
Pages
9210-8
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC3127548
Subset
IM
Grants
NIEHS NIH HHS · ES015567 · United States
NINDS NIH HHS · R01 NS060872-01A2 · United States
Intramural NIH HHS · Z01 AG000953 · United States
NIEHS NIH HHS · R01 ES015567-04 · United States
NINDS NIH HHS · R01 NS041786 · United States
NINDS NIH HHS · R01 NS060872 · United States
NIEHS NIH HHS · R01 ES015567-01A2 · United States
NINDS NIH HHS · R01 NS041786-01 · United States
NIEHS NIH HHS · R01 ES015567 · United States
NINDS NIH HHS · NS060872 · United States
External Links
PubMed source DOI: 10.1523/JNEUROSCI.2281-09.2009 PMC Full Text View journal details
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