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.

Regulation of DJ-1 by Glutaredoxin 1 in Vivo: Implications for Parkinson’s Disease

“…Compared to WT, the mutant djr-1.2 −/− worms displayed a late onset loss of dopamine-dependent behavior on adult day 2 (Figure 5B). These data are in agreement with the previous finding that dauer-stage C. elegans lacking djr-1.2 have a dopamine signaling defect [35]. Moreover, the hybrid lines, both deficient in DJR-1.2 and expressing G2019S or R1441C, displayed a more robust loss of dopamine-dependent behavior (Figure 5B).…”

“Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies”

“…Chronic manganese poisoning also led to significant impairment of learning processes[168] C. elegans 1 h Mn (10 or 25 mM) exposure on L1 larval stageBasal slowing responseMn-exposed worms had an impaired basal slowing response, indicating DAergic damage. This was reversed by SLC30A10 (a cell surface-localized Mn efflux transporter) expression in DAergic neurons[67] C. elegans 30 min Mn (50 mM) exposure on L1 larval stageDauer movementIn WT dauer worms, the locomotion was increased in the presence of Mn, indicating DA signaling impairment[161]Male and female Sprague-Dawley ratsPregnant females treated with Mn (2 mg/ml) in drinking water from the first day of pregnancy until PND20.MWMPND 21–25: Mn-exposed females displayed memory deficits in the probe trialPND 56–60: Mn-exposed males performed significantly worse in the acquisition trial. Females exposed to Mn displayed deficits in learning and memory[159]Three-month-old male Wistar ratsIntranasal 2-week-long MnCl 2 (0.8 mg/kg body weight)MWMSpatial memory deficits[160]Male Sprague-Dawley ratsIntraperitoneal injection of MnCl 2 15 mg/kg for 8, 12 or 18 weeksMWMEscaping latency and swimming distance of rats in the model groups increased, suggesting spatial learning and memory impairment[162]Male Sprague Dawley ratsIntraperitoneal injections of 0, 5, 10 and 20 mg/kg MnCl 2 once daily, 5 days/ week for 18 weeks.MWMMn impaired learning and memory as follow:In 6 weeks at dose 20 mg/kg.…”

Robust Glyoxalase activity of Hsp31, a ThiJ/DJ-1/PfpI Family Member Protein, Is Critical for Oxidative Stress Resistance in Saccharomyces cerevisiae

“…Additionally, DJ-1 has been shown recently to function as an oxidative stress sensor, and its absence leads to increased risk of oxidative stress in dopaminergic neurons of the substantia nigra (42). The homologs of DJ-1 are reported across other species, including Drosophila and Caenorhabditis elegans (43,44). In contrast to humans, Drosophila has two homologs, namely DJ-1␣ and DJ-1␤ (44).…”