Novel roles for the Parkinson's disease gene PINK1 in Drosophila
Abstract/Contents
- Abstract
- Parkinson's disease (PD) is the second most common neurodegenerative disorder and the second most common movement disorder in the world. It is progressive and disabling, and has no cure. An ever-increasing body of research suggests that mitochondrial dysfunction plays a key role in PD pathogenesis. For example, one cause of familial, early-onset PD is the loss of function of PINK1 (PTEN-induced putative kinase 1), a mitochondria-targeted serine/threonine kinase. In this dissertation, we ask how PINK1's loss of function affects mitochondrial health, and contributes to PD pathogenesis. We first sought to better understand the effects of PINK1's loss of function on mitochondrial transport by clarifying PINK1's relationship to a known target Miro, a motor adaptor critical for mitochondrial motility. We found that PINK1 mediates the phosphorylation of Miro at three specific sites, and that phosphorylation at these sites is critical for the health of dopaminergic neurons, synaptic growth at neuromuscular junctions, and mitochondrial motility in Drosophila. During this study, we established an in vivo method for identifying novel physiological functions of PINK1-mediated phosphorylation of its substrates, which we used in our second study. To expand our understanding of the cellular functions of PINK1, we employed an unbiased phosphoproteomic screen to identify potential novel targets. We were surprised to uncover a relationship between PINK1 and medium-chain acyl-CoA dehydrogenase (MCAD), an enzyme critical for the oxidation of fatty acids. Using methods developed in our first study, we found that PINK1 mediates the phosphorylation of MCAD at a specific serine site, and that phosphorylation at this site is critical to maintaining locomotor and morphological features in Drosophila. We also employed metabolic profiling and found that phosphorylation at this serine site is critical for the regulation of certain metabolites, and that PINK1's loss of function results in widespread disruption of metabolites in Drosophila. By uncovering novel physiological consequences of PINK1-mediated phosphorylation of Miro, we have further clarified PINK1's role in mitochondrial transport. By uncovering a novel relationship between PINK1 and MCAD, we have implicated PINK1 in metabolic homeostasis. Overall, by studying the functions of PINK1, we hope we have come one step closer to identifying biomarkers and therapeutic targets for PD, and to understanding the basis of its pathogenesis.
Description
Type of resource | text |
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Form | electronic; electronic resource; remote |
Extent | 1 online resource. |
Publication date | 2017 |
Issuance | monographic |
Language | English |
Creators/Contributors
Associated with | Course, Meredith Marie |
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Associated with | Stanford University, Neurosciences Program. |
Primary advisor | Wang, Xinnan |
Thesis advisor | Wang, Xinnan |
Thesis advisor | Clandinin, Thomas R. (Thomas Robert), 1970- |
Thesis advisor | Lu, Bingwei, 1968- |
Thesis advisor | Reimer, Richard J |
Advisor | Clandinin, Thomas R. (Thomas Robert), 1970- |
Advisor | Lu, Bingwei, 1968- |
Advisor | Reimer, Richard J |
Subjects
Genre | Theses |
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Bibliographic information
Statement of responsibility | Meredith Marie Course. |
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Note | Submitted to the Program in Neurosciences. |
Thesis | Thesis (Ph.D.)--Stanford University, 2017. |
Location | electronic resource |
Access conditions
- Copyright
- © 2017 by Meredith Marie Course
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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