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

Abstract

Parkinson's disease (PD) is a common neurodegenerative disorder that displays both sporadic and inherited forms. Exposure to several common environmental toxins acting through oxidative stress has been shown to be associated with PD. One recently identified inherited PD gene, DJ-1, may have a role in protection from oxidative stress, 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-1beta is ubiquitous, while DJ-1alpha is predominantly expressed in the male germline. DJ-1alpha and DJ-1beta 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-1beta 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-1beta protein is biochemically responsive to oxidative stress. Study of these flies will provide insight into the critical interplay of genetics and environment in PD.

Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging

“…Studies in cell culture and animal models suggest that DJ-1 protein responds to oxidative stress (23)(24)(25)(26)(27)(28)(29)(30)(31)(32), shifting to more acidic species (33,34). This includes oxidation of highly conserved cysteine residues, leading to the formation of cysteine sulfinic or sulfonic acids (35,36).…”

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…Reciprocally, DJͲ1 overexpression in these cells resulted in increased resistance to these insults and reduced intracellular ROS formation [272]. This protection seems to be selective against environmental oxidative stress in vivo, as shown in DJͲ1 null Drosophila treated with paraquat and rotenone [273]. Thus, DJͲ1ɴͲdeficient flies displayed a locomotor deficit that was exacerbated by oxidative stress [274].Furthermore, the levels of DJͲ1 modification increase with age, also leading to significant increments in oxidative stress and inactivation of its own function [275].…”

Tumours and tremors: how PTEN regulation underlies both

“…Significantly, this hypersensitivity to oxidative stress is also seen in the neurons of dj-1-deficient mice (Kim et al, 2005b). In both organisms, the increased susceptibility to oxidative stress can be rescued by activation of the PI3 0 K pathway (Kim et al, 2005b;Meulener et al, 2005;Yang et al, 2005). Other work has implicated DJ-1 as a sensor of reactive oxygen species and as a molecular chaperone (Shendelman et al, 2004), and DJ-1 may be able to influence the protein stability or oxidative state of elements of the PI3 0 K pathway.…”