RT Journal Article SR Electronic T1 LRRK2 Modulates Vulnerability to Mitochondrial Dysfunction in Caenorhabditis elegans JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 9210 OP 9218 DO 10.1523/JNEUROSCI.2281-09.2009 VO 29 IS 29 A1 Shamol Saha A1 Maria D. Guillily A1 Andrew Ferree A1 Joel Lanceta A1 Diane Chan A1 Joy Ghosh A1 Cindy H. Hsu A1 Lilach Segal A1 Kesav Raghavan A1 Kunihiro Matsumoto A1 Naoki Hisamoto A1 Tomoki Kuwahara A1 Takeshi Iwatsubo A1 Landon Moore A1 Lee Goldstein A1 Mark Cookson A1 Benjamin Wolozin YR 2009 UL http://www.jneurosci.org/content/29/29/9210.abstract AB 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.