Abstract
The loss of dopaminergic neurons in the substantia nigra is the pathological hallmark of Parkinson's disease (PD). While the etiology of sporadic PD remains elusive, an inherited form of early-onset familial PD is linked to mutations of DJ-1. To understand the biological function of DJ-1 and its relevance to the pathogenesis of PD, we investigated the function of DJ-1 using Drosophila. Drosophila possesses two homologs of human DJ-1: DJ-1alpha and DJ-1beta. We found that DJ-1alpha is expressed predominantly in the testis, while DJ-1beta is ubiquitously present in most tissues, resembling the expression pattern of human DJ-1. Loss-of-function DJ-1beta mutants demonstrated an extended survival of dopaminergic neurons and resistance to paraquat stress, but showed acute sensitivity to hydrogen peroxide treatment. We showed a compensatory upregulation of DJ-1alpha expression in the brain of the DJ-1beta mutant and demonstrated that overexpression of DJ-1alpha in dopaminergic neurons is sufficient to confer protection against paraquat insult. These results suggest that Drosophila homologs of DJ-1 play critical roles in the survival of dopaminergic neurons and response to oxidative stress.
