The putative multidrug resistance proteinMRP‐7 inhibits methylmercury‐associated animal toxicity and dopaminergic neurodegeneration inCaenorhabditis elegans

Abstract

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 (C. elegans) modulates whole animal and DA neuron sensitivity to MeHg. In this study we demonstrate that genetic knockdown of MRP-7 results in a 2-fold 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.

Exposome, Molecular Pathways and One Health: The Invertebrate Caenorhabditis elegans

“…Certain pollutants including manufactured nanomaterials likewise induce molecular cascades of neurodegeneration. It has been shown in dopaminergic and serotonergic neurons that manganese, methylmercury, or nano silica induce protein aggregation in axons and disturb trafficking of cargoes, such as mitochondria and neurotransmitters, to the synapse [ 23 , 61 , 62 , 63 ]. Due to a well-characterized neural wiring, the loss of neuronal functioning can be monitored in C. elegans by quantification of neuromuscular behaviors under the control of respective dopaminergic, GABAergic or serotonergic neurons [ 64 ].…”

Perspectives on C. elegans models of human Parkinson’s Disease

“…Therefore, once compounds pass into the pseudocoelomic space, exposure to neuronal cells can be immediate. C. elegans also has a family of multidrug resistant proteins to exclude unwanted chemicals from entering cells [22].…”