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The Journal of Neuroscience, July 22, 2009, 29(29):9210-9218; doi:10.1523/JNEUROSCI.2281-09.2009

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Neurobiology of Disease
LRRK2 Modulates Vulnerability to Mitochondrial Dysfunction in Caenorhabditis elegans

Shamol Saha,¹ Maria D. Guillily,^1 * Andrew Ferree,^1 * Joel Lanceta,¹ Diane Chan,¹ Joy Ghosh,² Cindy H. Hsu,¹ Lilach Segal,¹ Kesav Raghavan,¹ Kunihiro Matsumoto,⁵ Naoki Hisamoto,⁵ Tomoki Kuwahara,⁶ Takeshi Iwatsubo,⁶ Landon Moore,³ Lee Goldstein,² Mark Cookson,⁷ and Benjamin Wolozin^1,4

¹Departments of Pharmacology, ²Psychiatry, ³Medicine, and ⁴Neurology, Boston University School of Medicine, Boston, Massachusetts 02118, ⁵Department of Molecular Biology, Institute for Advanced Research, Nagoya University, Nagoya 464-8602, Japan, ⁶Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Science, University of Tokyo, Tokyo 113-0033, Japan, and ⁷Cell Biology and Gene Expression Unit, Laboratory of Neurogenetics, National Institute of Aging, Bethesda, Maryland 20892

Correspondence should be addressed to Dr. Benjamin Wolozin, Department of Pharmacology, Boston University School of Medicine, 72 E. Concord Street, R614, Boston, MA 02118-2526. Email: bwolozin{at}bu.edu

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.

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Received May 14, 2009; revised June 11, 2009; accepted June 17, 2009.

Correspondence should be addressed to Dr. Benjamin Wolozin, Department of Pharmacology, Boston University School of Medicine, 72 E. Concord Street, R614, Boston, MA 02118-2526. Email: bwolozin{at}bu.edu

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