RRC ID 45703
著者 Chen P, DeWitt MR, Bornhorst J, Soares FA, Mukhopadhyay S, Bowman AB, Aschner M.
タイトル Age- and manganese-dependent modulation of dopaminergic phenotypes in a C. elegans DJ-1 genetic model of Parkinson's disease.
ジャーナル Metallomics
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.
巻・号 7(2)
ページ 289-98
公開日 2015-2-1
DOI 10.1039/c4mt00292j
PMID 25531510
PMC PMC4479152
MeSH Aging / pathology* Aldehyde Oxidoreductases / metabolism* Animals Caenorhabditis elegans / drug effects Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / metabolism* Disease Models, Animal Dopaminergic Neurons / drug effects Dopaminergic Neurons / metabolism Dopaminergic Neurons / pathology* Forkhead Transcription Factors / metabolism Gene Deletion Green Fluorescent Proteins / metabolism Longevity / drug effects Manganese / pharmacology* Models, Biological Models, Genetic* Movement / drug effects Parkinson Disease / genetics Parkinson Disease / pathology* Phenotype Signal Transduction / drug effects Survival Analysis
IF 3.796
引用数 26
WOS 分野 BIOCHEMISTRY & MOLECULAR BIOLOGY
リソース情報
線虫 tm918 tm1346