This competitive ViCTER supplemental application builds on the fundamental premise of the parent grant: to explore the potential neurological effects of life time exposure to low levels of methyl mercury (MeHg) as might occur by regular seafood consumption, especially interactions between MeHg and consequences for the brain during aging. An interactive consortium consisting of investigators at three institutions will be formed to study the effects of chronic low dose exposure to MeHg on nigrostriatal dopamine (NSDA) neuronal function. Parkinson'sdisease (PD) is a chronic, progressive neurodegenerative disorder associated with senescence. PD is characterized by degeneration and dysfunction of NSDA neurons, which underly the clinical symptoms of Parkinsonism (tremor, motor slowing and distortions in motor timing). Genetic mutations have been identified in familial PD, but most PD is sporadic and substantial epidemiological evidence suggests a role for environmental contaminants, but, to date no specific environmental agent has been shown unequivocally to be causative. MeHg accumulates in basal ganglia, a region associated with regulating motor timing and speed and can distort NSDA neuronalfunction.Thus chronic, low-level MeHg exposure could facilitate development of NSDA dysfunction leading to PD-like effects, especially in patients with genetic or age-related susceptibility. The application is based on the discovery that cell bodies in the substantial nigra pars compact (SNpc) exhibit intrinsic pacemaking firing activity that may predispose them to Ca2+-mediated cell death, a trait that depends on Cav1.3 L-type voltage-gated Ca2+ channels. Our central hypothesis holds that MeHg exposure disrupts NSDA function by interacting with L-type Ca2+ channels and altering [Ca2+]i homeostasis.To test this, the investigators will determine whether an L-type channel antagonist, isradipine, delays MeHg-induced neurotoxicity in vitro and reduces the severity of MeHg toxicity in vivo. The investigators hypothesize that isradipine will delay or blunt the deleterious effects of MeHg on NSDA function. At Auburn University, behavioral analyses of MeHg-treated mice and dopaminergic drug challenges will test for MeHg-induced effects on temporal perception and motor function. At Indiana University, the molecular genetics of proteins associated with dopamine (DA) cell function and Ca2+-mediated cell death coupled with cell specific cytotoxicity will entail use of C. elegans. The proposed functional studies will be done at Michigan State University and entail electrophysiological analyses of Ca2+ channel function, analysis of DA homeostasis and single cell imaging of NSDA neurons. Fluorescence changes in [Ca2+]i and mitochondrial Ca2+ in SNpc cells will be analyzed in isolated slices from mice at various stages of MeHg exposure. Cellular studies will also make use of a knock-out mouse for the Cav1.3 Ca2+ channel, which exhibits a SNpc firing pattern phenotype that diminishes the stress placed on [Ca2+]i regulation in these neurons. The present proposal will leverage the resources of the parent grant to determine whether chronic adult-onset (lifetime) exposure to MeHg hastens age-associated NSDA neuronal dysfunction, in addition to assessing the ability of Ca2+ channel blockers to mitigate this dysfunction.
Environmental exposure are postulated to contribute to the sporadic form of the progressive neurodegenerative diseaseParkinson'sDisease(PD).UniquefeaturesofsusceptibleneuronsinPDmakethempotentiallyvulnerable to toxic agents. The present proposal is designed to test if the environmental metal mercury hastens the developmental of PD by interaction with these vulnerable targets.
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