Human Molecular Genetics Advance Access originally published online on August 19, 2009
Human Molecular Genetics 2009 18(22):4390-4404; doi:10.1093/hmg/ddp394
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Leucine-rich repeat kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease
1 Ottawa Health Research Institute, Neuroscience Research Institute, 451 Smyth Rd, Ottawa, Ontario, Canada K1H 8M5, 2 Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5, 3 Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan, 4 Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA, 5 Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA, 6 Center for Research in Neuroscience, University McGill, Montreal, Quebec, Canada H3G 1A4 and 7 Burnham Institute for Medical Research, La Jolla, CA 92037, USA
* To whom correspondence should be addressed. Tel: +1 6135625800 extn 8816; Fax: +1 6135625403; Email: dpark{at}uottawa.ca (D.S.P.); ehaque{at}uottawa.ca (M.E.H.)
Received July 23, 2009; Revised July 23, 2009; Accepted August 13, 2009
Mutations in the LRRK2 gene are the most common genetic cause of familial Parkinson's disease (PD). However, its physiological and pathological functions are unknown. Therefore, we generated several independent Drosophila lines carrying WT or mutant human LRRK2 (mutations in kinase, COR or LRR domains, resp.). Ectopic expression of WT or mutant LRRK2 in dopaminergic neurons caused their significant loss accompanied by complex age-dependent changes in locomotor activity. Overall, the ubiquitous expression of LRRK2 increased lifespan and fertility of the flies. However, these flies were more sensitive to rotenone. LRRK2 expression in the eye exacerbated retinal degeneration. Importantly, in double transgenic flies, various indices of the eye and dopaminergic survival were modified in a complex fashion by a concomitant expression of PINK1, DJ-1 or Parkin. This evidence suggests a genetic interaction between these PD-relevant genes.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.