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Published online on January 8, 2008, 10.1073/pnas.0711018105
PNAS | January 15, 2008 | vol. 105 | no. 2 | 728-733


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BIOLOGICAL SCIENCES / NEUROSCIENCE
Hypothesis-based RNAi screening identifies neuroprotective genes in a Parkinson's disease model

Shusei Hamamichi*, Renee N. Rivas*, Adam L. Knight*, Songsong Cao*, Kim A. Caldwell*,{dagger}, and Guy A. Caldwell*,{dagger},{ddagger}

*Department of Biological Sciences, University of Alabama, Tuscaloosa, AL 35487; and {dagger}Departments of Neurology and Neurobiology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL 35294

Communicated by Susan L. Lindquist, Whitehead Institute for Biomedical Research, Cambridge, MA, November 27, 2007 (received for review October 2, 2007)

Genomic multiplication of the locus-encoding human {alpha}-synuclein ({alpha}-syn), a polypeptide with a propensity toward intracellular misfolding, results in Parkinson's disease (PD). Here we report the results from systematic screening of nearly 900 candidate genetic targets, prioritized by bioinformatic associations to existing PD genes and pathways, via RNAi knockdown. Depletion of 20 gene products reproducibly enhanced misfolding of {alpha}-syn over the course of aging in the nematode Caenorhabditis elegans. Subsequent functional analysis of seven positive targets revealed five previously unreported gene products that significantly protect against age- and dose-dependent {alpha}-syn-induced degeneration in the dopamine neurons of transgenic worms. These include two trafficking proteins, a conserved cellular scaffold-type protein that modulates G protein signaling, a protein of unknown function, and one gene reported to cause neurodegeneration in knockout mice. These data represent putative genetic susceptibility loci and potential therapeutic targets for PD, a movement disorder affecting {approx}2% of the population over 65 years of age.

Caenorhabditis elegans | neuroprotection | synuclein

Author contributions: S.H., K.A.C., and G.A.C. designed research; S.H., R.N.R., and A.L.K. performed research; S.H. and S.C. contributed new reagents/analytic tools; S.H., K.A.C., and G.A.C. analyzed data; and S.H., K.A.C., and G.A.C. wrote the paper.

Conflict of interest statement: G.A.C. and K.A.C. serve as scientific advisors to QRxPharma, Ltd., from whom they receive monetary compensation and a sponsored research agreement.

This article contains supporting information online at www.pnas.org/cgi/content/full/0711018105/DC1.

{ddagger}To whom correspondence should be sent at the * address. E-mail: gcaldwel{at}bama.ua.edu

© 2008 by The National Academy of Sciences of the USA


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