Drosophila DJ-1 Mutants Are Selectively Sensitive to Environmental Toxins Associated with Parkinson’s Disease

• Published in: Current biology 2005-09, Vol.15 (17), p.1572-1577
• Main Authors: Meulener, Marc, Whitworth, Alexander J., Armstrong-Gold, Cecilia E., Rizzu, Patrizia, Heutink, Peter, Wes, Paul D., Pallanck, Leo J., Bonini, Nancy M.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Animals, Genetically Modified; Blotting, Western; Cluster Analysis; Computational Biology; Crosses, Genetic; Drosophila; Drosophila Proteins - genetics; Molecular Sequence Data; Mutation - genetics; Nerve Tissue Proteins - genetics; Neurons - drug effects; Oxidative Stress - drug effects; Paraquat - toxicity; Parkinson Disease - genetics; Parkinson Disease - metabolism; Phylogeny; Rotenone - toxicity; Sequence Alignment; Survival Analysis
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2005.07.064

Parkinson’s disease (PD) is a common neurodegenerative disorder that displays both sporadic and inherited forms [ 1]. Exposure to several common environmental toxins acting through oxidative stress has been shown to be associated with PD [ 2]. One recently identified inherited PD gene, DJ-1, may have a role in protection from oxidative stress [ 3–10], thus potentially linking a genetic cause with critical environmental risk factors. To develop an animal model that would allow integrative study of genetic and environmental influences, we have generated Drosophila lacking DJ-1 function. Fly DJ-1 homologs exhibit differential expression: DJ-1β is ubiquitous, while DJ-1α is predominantly expressed in the male germline. DJ-1α and DJ-1β double knockout flies are viable, fertile, and have a normal lifespan; however, they display a striking selective sensitivity to those environmental agents, including paraquat and rotenone, linked to PD in humans. This sensitivity results primarily from loss of DJ-1β protein, which also becomes modified upon oxidative stress. These studies demonstrate that fly DJ-1 activity is selectively involved in protection from environmental oxidative insult in vivo and that the DJ-1β protein is biochemically responsive to oxidative stress. Study of these flies will provide insight into the critical interplay of genetics and environment in PD.