Characterization of Vesicular Monoamine Transporter 2 and Its Role In Parkinson'S Disease Pathogenesis Using Drosophila

<p>Parkinson’s disease (PD) is a progressive neurodegenerative disorder caused by the selective loss of the dopaminergic neurons in the <em>S</em><em>ubstantia nigra</em><em> pars compacta</em> region of the brain. PD is also the most common neurodegenerative disorder and the second most common movement disorder. PD patients exhibit the cardinal symptoms, including tremor of the extremities, rigidity, slowness of movement, and postural instability, after 70-80% of DA neurons degenerate. It is, therefore, imperative to elucidate the underlying mechanisms involved in the selective degeneration of DA neurons. Although increasing numbers of PD genes have been identified, why these largely widely expressed genes induce selective loss of DA neurons is still not known. Notably, dopamine (DA) itself is a chemically labile molecule and can become oxidized to toxic by-products while induce the accumulation of harmful molecules such as Reactive Oxygen Species (ROS). Accordingly, DA toxicity has long been suspected to play a role in selective neuronal loss in PD. Vesicular Monoamine Transporter (VMAT) is essential for proper vesicular storage of monoamines such as DA and their regulated release. Increasing evidence have linked VMAT dysfunction with Parkinson’s disease. In this study, we re-examine the gain- and loss-of-function phenotypes of the sole VMAT homologue in <em>Drosophila</em>. Our results suggest that the C-terminal sequences in the two encoded VMAT isoforms not only determine their differential subcellular localizations, but also their activities in content release. In particular, VMAT2 orthologue potentially poses a unique, previously unexplored activity in promoting DA release. On the other hand, by examining DA distribution in wildtype and <em>VMAT</em> mutant animals, we find that there exists intrinsic difference in the dynamics of intracellular DA handling among DA neurons clustered in different brain regions. Furthermore, loss of VMAT causes severe loss of total DA levels and a redistribution of DA in <em>Drosophila</em> brain. Lastly, removal of both VMAT and another PD gene <em>parkin, </em>which is also conserved in <em>Drosophila, </em>results in the selective loss of DA neurons, primarily in the protocerebral anterior medial (PAM) clusters of the brain. Our results suggest a potential involvement of cytoplasmic DA in selective degeneration of DA neurons and also implicating a role for a differential intracellular DA handling mechanism underlying the regional specificity of neuronal loss in PD patients.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2016

Authors dc:creator

• Tito, Antonio Joel, Jr.
• Zhang, Sheng

Contributors dc:contributor

• Sheng Zhang, Ph.D.
• Richard Behringer, Ph.D.
• Hugo Bellen, Ph.D.

• Neuroscience
• Neurodegenerative Disease
• Drosophila
• Brain
• Dopamine Neurons
• Dopamine
• Parkinson's Disease
• Parkin
• VMAT
• Cell Biology
• Medicine and Health Sciences
• Molecular and Cellular Neuroscience
• Molecular Biology
• Molecular Genetics

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/719

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1763