Parkinson’s disease (PD) is the second most commonly occurring neurodegenerative disease. It is characterized by motor dysfunctions resulting from a deficiency of dopamine in the striatum caused by degeneration of dopaminergic (DAergic) neurons in the nigrostriatal pathway. While there is no cure for PD, L-DOPA is commonly prescribed to alleviate the motor symptoms by restoring dopamine in the striatum. However, L-DOPA may jeopardize the health of the remaining neurons based on evidence that dopamine handling is dysregulated in PD, which is likely the result of deficient vesicular sequestration by the vesicular monoamine transporter 2 (VMAT2). Accordingly, VMAT2 mRNA, protein, and activity are decreased in PD patients. Deficits in vesicular sequestration result in cytosolic dopamine, which is detrimental to neuronal health due to two processes – metabolism and oxidation – which generate reactive metabolites and cause oxidative stress. It is vital to investigate the consequence of impaired dopamine sequestration to understand the pathogenesis of PD and to understand how to approach therapeutic intervention in PD.
This dissertation research studied the effect of viral-mediated decreased VMAT2 expression on neuronal health. A decrease in VMAT2 resulted in increased dopamine metabolism and oxidation, deficits in dopamine-mediated behaviors, generation of aberrant α-synuclein, activation of PD-associated kinase LRRK2, and a loss of DAergic neurons in the SNpc with a corresponding degeneration of DAergic terminals in the striatum. The loss of DAergic neurons following decreased endogenous VMAT2 was rescued by reintroducing exogenous VMAT2. These data suggest that decreasing VMAT2 expression is sufficient to induce PD associated pathogenic mechanisms of neurodegeneration, further implicating the role of dysfunctional dopamine packaging in the pathogenesis of PD. Given the toxic potential of cytosolic dopamine observed, the hypothesis that increased sequestration of dopamine would be protective against nigrostriatal degeneration in a PD model was tested. While we were able to successfully demonstrate viral-mediated overexpression of VMAT2, we were unable to detect VMAT2 overexpression-mediated protection. This data is in disagreement with previous in vivo studies and is likely due to limitations of our model.
|Advisor:||Hastings, Teresa G|
|Commitee:||Greenamyre, J Timothy, Berman, Sarah, Aizenman, Elias, Seal, Rebecca, Lawal, Hakeem|
|School:||University of Pittsburgh|
|Department:||Dietrich School Arts and Sciences|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 81/8(E), Dissertation Abstracts International|
|Keywords:||Dopamine, Neurodegeneration, Oxidative stress, Parkinson's disease|
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