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The putative multidrug resistance protein MRP ‐7 inhibits methylmercury‐associated animal toxicity and dopaminergic neurodegeneration in Caenorhabditis elegans
Author(s) -
VanDuyn Natalia,
Nass Richard
Publication year - 2014
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12515
Subject(s) - substantia nigra , caenorhabditis elegans , neurodegeneration , biology , pars compacta , dopaminergic , gene knockdown , neurotoxicity , microbiology and biotechnology , dopamine , genetics , gene , neuroscience , toxicity , pathology , medicine , disease
Parkinson's disease ( PD ) is the most prevalent neurodegenerative motor disorder worldwide, and results in the progressive loss of dopamine ( DA ) neurons in the substantia nigra pars compacta. Gene–environment interactions are believed to play a significant role in the vast majority of PD cases, yet the toxicants and the associated genes involved in the neuropathology are largely ill‐defined. Recent epidemiological and biochemical evidence suggests that methylmercury (MeHg) may be an environmental toxicant that contributes to the development of PD . Here, we report that a gene coding for the putative multidrug resistance protein MRP ‐7 in Caenorhabditis elegans modulates whole animal and DA neuron sensitivity to MeHg. In this study, we demonstrate that genetic knockdown of MRP ‐7 results in a twofold increase in Hg levels and a dramatic increase in stress response proteins associated with the endoplasmic reticulum, golgi apparatus, and mitochondria, as well as an increase in MeHg‐associated animal death. Chronic exposure to low concentrations of MeHg induces MRP ‐7 gene expression, while exposures in MRP ‐7 genetic knockdown animals results in a loss of DA neuron integrity without affecting whole animal viability. Furthermore, transgenic animals expressing a fluorescent reporter behind the endogenous MRP ‐7 promoter indicate that the transporter is expressed in DA neurons. These studies show for the first time that a multidrug resistance protein is expressed in DA neurons, and its expression inhibits MeHg‐associated DA neuron pathology.Methylmercury (MeHg) exposure is a risk factor for Parkinson's disease. Yet, the molecular basis for Hg transport and neurotoxicity is poorly defined. Our studies identify the first multidrug resistance protein that is targeted to dopamine (DA) neurons. We show that the transporter inhibits MeHg‐associated accumulation of Hg, intracellular toxicant‐associated stress response, and DA neurodegeneration. This model should facilitate the identification of molecular pathways and potential therapeutic targets involved in MeHg‐associated dopamine neuron pathology. hsp = heat‐shock protein.