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Role of Ca2+ and Sodium-Calcium exchanger (NCX) on cellular/mitochondrial uptake and toxicity of the parkinsonian toxin, MPP+
Mapa, Mapa S.T.
Mapa, Mapa S.T.
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dissertation
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2016-12
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Dissertation
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Parkinson's disease,Dopaminergic neurons,Dopaminergic cells,Dopaminergic transporter,Reactive oxygen species,Central nervous system
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Electronic dissertations
Electronic dissertations
Electronic dissertations
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Abstract
Although the exact cause(s) of dopaminergic cell death in Parkinson's disease (PD) is not
fully understood, the discovery that 1-methyl-4-phenylpyridinium (MPP+
) selectively destroys
dopaminergic neurons and causes PD symptoms in humans and other mammals has strengthened
the environmental hypothesis of PD. The current model for the toxicity of MPP+ is centered on
its specific uptake into dopaminergic cells through the dopamine transporter (DAT), electrogenic
accumulation into the mitochondria, inhibition of the mitochondrial complex I, leading to ATP
depletion, increased reactive oxygen species (ROS) production, and apoptotic cell death.
However, MPP+
is taken up into many cell types through a number of other transporters,
challenging the major hypothesis of this model, that the specific dopaminergic toxicity of MPP+
is due to the specific uptake through DAT. In order to address this discrepancy, we have
characterized a series of 4'-substituted MPP+
derivatives with varying hydrophilicities. The
photophysical studies of these derivatives show that 4'I-MPP+
is fluorescent and can be used to
localize the intracellular distribution of MPP+
. Using these novel probes, we have shown that
both cellular and mitochondrial uptake of MPP+ are modulated by the cell and mitochondrial
membrane potentials and found that Ca2+ play a key role in these MPP+
uptakes and toxicities.
Furthermore, the effects of Ca2+ on MPP+
uptake and toxicity are mediated through
mitochondrial and plasma membrane sodium calcium-exchangers (NCX) and the mitochondrial
permeability transition pore (PTP). For the first time, we show that the specific mitochondrial
NCX (mNCX) inhibitor, CGP37157 inhibits mitochondrial uptake of MPP+
and protects
dopaminergic MN9D cells from MPP+
toxicity. Thus, these findings could be further exploited
for development of pharmacological agents to protect central nervous system (CNS)
dopaminergic neurons from PD-causing environmental toxins.
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Thesis (Ph.D.)-- Wichita State University, Fairmount College of Liberal Arts and Sciences, Dept. of Chemistry
Publisher
Wichita State University
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Copyright 2016 by Mapa S. T. Mapa