Buck, Silas Alexander
(2023)
Mechanisms of Vesicular Glutamate Transporter-Mediated Dopamine Neuron Resilience to Parkinson's Disease Models.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Parkinson’s disease (PD) is characterized by dopamine (DA) neuron degeneration in the substantia nigra pars compacta (SNc), which leads to motor dysfunction. Interestingly, not all DA neurons are equally vulnerable to degeneration in PD, as neighboring DA neurons in the ventral tegmental area (VTA) and substantia nigra pars lateralis, or lateral SNc, are relatively protected. One key to uncovering this resilience may lie in the discovery that a minority of DA neurons co-express vesicular glutamate transporter 2 (VGLUT2), which is necessary and sufficient for release of glutamate as a second neurotransmitter in addition to DA. Much higher proportions of VTA and substantia nigra pars lateralis DA neurons co-express VGLUT2 compared to the SNc, and DA neuron VGLUT2 expression is associated with resilience to animal models of PD and human PD. Further, studies show that modulating DA neuron VGLUT2 expression directly impacts cell vulnerability in PD models. To date, however, the mechanism by which VGLUT2 confers protection in DA neurons is unknown.
In this dissertation, we first expand on findings of VGLUT2-associated DA neuroprotection by measuring DA neuron VGLUT2 expression in rats after exposure to rotenone, a mitochondrial Complex I-inhibiting model of PD. We found that, as in previous PD models tested, VGLUT2 expression is associated with DA neuron resilience, particularly in the substantia nigra pars lateralis. To begin testing mechanisms of VGLUT2-associated resilience, we used the genetically tractable Drosophila melanogaster (fruit fly) animal model. First, we established that fly DA neurons express the Drosophila ortholog of VGLUT2, Drosophila VGLUT (dVGLUT). We then found that knocking down dVGLUT expression in DA neurons increases vulnerability to DA neuron degeneration. To determine dVGLUT-mediated mechanisms of resilience, we created DA neuron-targeted fluorescent reporters to test whether dVGLUT mediates mitochondrial function and mitochondrial vulnerability to PD-associated stress. Finally, we screened genes differentially expressed in dVGLUT-expressing DA neurons to identify additional mediators of DA neuron resilience and vulnerability in dVGLUT-positive DA neurons.
Together, these findings establish VGLUT is a key driver of DA neuron resilience in models of PD. Future work exploiting these mechanisms of protection may elucidate novel treatments for PD-associated DA neuron degeneration.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
17 November 2023 |
| Date Type: |
Publication |
| Defense Date: |
13 July 2023 |
| Approval Date: |
17 November 2023 |
| Submission Date: |
18 July 2023 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
262 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Neurobiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Dopamine
Parkinson's
Drosophila
VGLUT
VGLUT2
dVGLUT
Neurodegeneration
Paraquat
Rotenone
Aging |
| Date Deposited: |
17 Nov 2023 19:02 |
| Last Modified: |
17 Nov 2023 19:02 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/45108 |
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