Parkinson's disease (PD) is a neurodegenerative disorder affecting over a million Americans. The prevalence of PD will grow as the population ages. The central neuropathological feature in PD is the selective loss of pigmented dopaminergic neurons in the substantia nigra (SN). Why or how the SN neuron- specific vulnerability in PD occurs at the molecular level is not known. Exogenous/endogenous environmental neurotoxins and genetic susceptibility are suspected in the vast majority of PD cases and each is exaggerated by aging. Postulated mechanisms include oxidative stress, mitochondrial dysfunction, neurotrophic deficiency, inflammatory reaction and excitotoxicity. Unfortunately, there are no established molecular indicators nor appropriate model systems to assess the pathological processes triggered by developmental exposure to environmental neurotoxins. We hypothesize that exposure to environmental neurotoxins during dopaminergic development enhances the susceptibility to accelerated dopaminergic cell death during aging via the common molecular mechanism(s) of the alteration of stress-activated signal transduction pathways, expression of differentiation transcription factors, survival factors or phenotype marker proteins in the nigral dopaminergic neurons. To test the hypothesis, we adopt our newly established, unique model system of in vitro SN dopaminergic development using an embryonic dopaminergic progenitor cell line. In the model cell line, three distinct developmental and aging stages, proliferation, differentiation and aging cell death, can be induced by environmental cues in vitro. The feasibility of this in vitro model system to monitor various pathological molecular indicators during each developmental stage will be pilot tested using both the known and the potential dopaminergic environmental neurotoxins.
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| Chun, H S; Son, J J; Son, J H (2000) Identification of potential compounds promoting BDNF production in nigral dopaminergic neurons: clinical implication in Parkinson's disease. Neuroreport 11:511-4 |
