Age- and manganese-dependent modulation of dopaminergic phenotypes in a C. elegans DJ-1 genetic model of Parkinson's disease

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease, yet its etiology and pathogenesis are poorly understood. PD is characterized by selective dopaminergic (DAergic) degeneration and progressive hypokinetic motor impairment. Mutations in dj-1 cause autosomal recessive early-onset PD. DJ-1 is thought to protect DAergic neurons via an antioxidant mechanism, but the precise basis of this protection has not yet been resolved. Aging and manganese (Mn) exposure are significant non-genetic risk factors for PD. Caenorhabditis elegans (C. elegans) is an optimal model for PD and aging studies because of its simple nervous system, conserved DAergic machinery, and short 20-day lifespan. Here we tested the hypothesis that C. elegans DJ-1 homologues were protective against Mn-induced DAergic toxicity in an age-dependent manner. We showed that the deletion of C. elegans DJ-1 related (djr) genes, djr-1.2, decreased survival after Mn exposure. djr-1.2, the DJ-1 homologue was expressed in DAergic neurons and its deletion decreased lifespan and dopamine (DA)-dependent dauer movement behavior after Mn exposure. We also tested the role of DAF-16 as a regulator of dj-1.2 interaction with Mn toxicity. Lifespan defects resulting from djr-1.2 deletion could be restored to normal by overexpression of either DJR-1.2 or DAF-16. Furthermore, dauer movement alterations after djr-1.2 deletion were abolished by constitutive activation of DAF-16 through mutation of its inhibitor, DAF-2 insulin receptor. Taken together, our results reveal PD-relevant interactions between aging, the PD environmental risk factor manganese, and homologues of the established PD genetic risk factor DJ-1. Our data demonstrate a novel role for the DJ-1 homologue, djr-1.2, in mitigating Mn-dependent lifespan reduction and DA signaling alterations, involving DAF-2/DAF-16 signaling.