Environmental & Pharmaceutical Exposures alter the function of VMAT2 and Promote Neurodegeneration in Parkinson's Disease Público
Jonas, Lauren Alexandra (2016)
Published
Abstract
Parkinson's disease (PD) is characterized by the gradual loss of dopaminergic neurons in the substantia nigra (SNc). Dopaminergic neurons located within the SNc innervate the dorsal striatum in both the direct and indirect striatal pathways within the basal ganglia and allow for balanced and smooth muscle movements. A breakdown of this pathway leads to many of the features associated with PD. While there are several genetic mutations associated with PD, both genetic and environmental factors are thought to contribute to the pathogenesis of Parkinson's disease. Dopamine is one of the main neurotransmitters involved in the mediation of balanced motor movements in a normal patient. Altered regulation of dopamine is involved in the disturbed motor movements in Parkinson's patients. This altered regulation can come in many forms; however, this thesis assesses environmental and pharmaceutical exposures that may alter the packaging and storage of dopamine by the vesicular monoamine transporter 2 (VMAT2) into small synaptic vesicles of the dopaminergic nerve terminals. Many studies have linked the disruption of VMAT2 to PD and this research serves to screen a number of compounds including PCBs, pesticides and drugs thought to alter dopamine storage. FFN206 was used as a VMAT2 substrate to perform high throughput screens of VMAT2-tranfected HEK-293 cell uptake activity. By employing this assay we were able to visualize significant decreased VMAT2 uptake activity in the compounds paraquat, rotenone, deltamethrin, Aroclor 1260, methylphenidate and methamphetamine. These data furthermore reveal a pathway that must be further analyzed in regards to toxicant exposure and PD. Additional investigation of these compounds and other compounds are necessary to fully understand the mechanisms of these toxicants; however, in light of these findings, we propose that further study of the role of environmental and pharmaceutical exposures on VMAT2 activity and the pathogenesis of PD is warranted.
Table of Contents
Background...........................................................1
Dopamine.............................................................4
VMAT2 Disruption leads to Neurodegeneration.......6
MPTP....................................................................7
Polychlorinated Biphenyls......................................8
Paraquat..............................................................11
Rotenone.............................................................12
Deltamethrin.......................................................13
Hypothesis...........................................................15
Materials and Methods..........................................15
Results.................................................................20
Characterization of HEK293 stable cell line ............20
Experimental Screen of Environmental and
Pharmaceutical Exposures....................................25
Examination of Environmental and
Occupational Exposures........................................26
Examination of Pharmaceutical Exposures.............28
Discussion............................................................31
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