QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, September 9, 2009, 29(36):11257-11262; doi:10.1523/JNEUROSCI.2375-09.2009

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Related articles in J. Neurosci. Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ng, C.-H. Articles by Lim, K.-L. Search for Related Content PubMed PubMed Citation Articles by Ng, C.-H. Articles by Lim, K.-L.

 Previous Article  |  Next Article 

Brief Communications
Parkin Protects against LRRK2 G2019S Mutant-Induced Dopaminergic Neurodegeneration in Drosophila

Chee-Hoe Ng,¹ Shaun Z. S. Mok,¹ Cherlyn Koh,¹ Xuezhi Ouyang,² Marc L. Fivaz,³ Eng-King Tan,^1,3 Valina L. Dawson,⁶ Ted M. Dawson,⁶ Fengwei Yu,^2,4 and Kah-Leong Lim^1,3,5

¹National Neuroscience Institute, Singapore 308433, ²Temasek Life Sciences Laboratory, Singapore 117604, ³Duke–NUS Graduate Medical School, Singapore 169857, Departments of ⁴Biological Sciences and ⁵Physiology, National University of Singapore, Singapore 119077, and ⁶Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Department of Neurology, Solomon H. Snyder Department of Neuroscience, and Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Correspondence should be addressed to Dr. Kah-Leong Lim, Neurodegeneration Research Laboratory, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433. Email: Kah_Leong_Lim{at}nni.com.sg or Email: kahleong.lim{at}duke-nus.edu.sg

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are currently recognized as the most common genetic cause of parkinsonism. Among the large number of LRRK2 mutations identified to date, the G2019S variant is the most common. In Asia, however, another LRRK2 variant, G2385R, appears to occur more frequently. To better understand the contribution of different LRRK2 variants toward disease pathogenesis, we generated transgenic Drosophila over-expressing various human LRRK2 alleles, including wild type, G2019S, Y1699C, and G2385R LRRK2. We found that transgenic flies harboring G2019S, Y1699C, or G2385R LRRK2 variant, but not the wild-type protein, exhibit late-onset loss of dopaminergic (DA) neurons in selected clusters that is accompanied by locomotion deficits. Furthermore, LRRK2 mutant flies also display reduced lifespan and increased sensitivity to rotenone, a mitochondrial complex I inhibitor. Importantly, coexpression of human parkin in LRRK2 G2019S-expressing flies provides significant protection against DA neurodegeneration that occurs with age or in response to rotenone. Together, our results suggest a potential link between LRRK2, parkin, and mitochondria in the pathogenesis of LRRK2-related parkinsonism.

---

Received May 21, 2009; revised July 30, 2009; accepted Aug. 3, 2009.

Correspondence should be addressed to Dr. Kah-Leong Lim, Neurodegeneration Research Laboratory, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433. Email: Kah_Leong_Lim{at}nni.com.sg or Email: kahleong.lim{at}duke-nus.edu.sg

Related articles in J. Neurosci.:

Unraveling LRRK2 Pathogenesis: Common Pathways for Complex Genes?

Emma Deas and Laura Dunn
J. Neurosci. 2010 30: 1577-1579. [Full Text]  

This article has been cited by other articles:

				E. Deas and L. Dunn Unraveling LRRK2 Pathogenesis: Common Pathways for Complex Genes? J. Neurosci., February 3, 2010; 30(5): 1577 - 1579. [Full Text] [PDF]

				X. Li, J. C. Patel, J. Wang, M. V. Avshalumov, C. Nicholson, J. D. Buxbaum, G. A. Elder, M. E. Rice, and Z. Yue Enhanced Striatal Dopamine Transmission and Motor Performance with LRRK2 Overexpression in Mice Is Eliminated by Familial Parkinson's Disease Mutation G2019S J. Neurosci., February 3, 2010; 30(5): 1788 - 1797. [Abstract] [Full Text] [PDF]

				E. Andres-Mateos, R. Mejias, M. Sasaki, X. Li, B. M. Lin, S. Biskup, L. Zhang, R. Banerjee, B. Thomas, L. Yang, et al. Unexpected Lack of Hypersensitivity in LRRK2 Knock-Out Mice to MPTP (1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine) J. Neurosci., December 16, 2009; 29(50): 15846 - 15850. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help