Investigating mitochondrial transport and quality control in drosophila melanogater models of neurodegenerative disease
Abstract/Contents
- Abstract
- Mitochondria are the major source of cellular ATP in eukaryotic cells and play several roles critical to cellular health and functionality including Ca2+ buffering and cell death signaling. Neurons have complex architectures with specialized subcompartments and local energetic and metabolic needs. To ensure constant mitochondrial integrity and supply, neurons rely on axonal transport of mitochondria, fission, fusion, and mitophagy. Evidence suggests that neurons with particularly long axons, high metabolic demands, or toxic loads may be more vulnerable to defects in mitochondrial transport or quality control processes. Parkinson's Disease and Amyotrophic Lateral Sclerosis are just two neurodegenerative diseases associated with defects in mitochondrial dynamics. In this dissertation, we address the role of mitochondrial transport and quality control in Drosophila models of neurodegenerative disease. In particular, we investigate Valosin Containing Protein (VCP/p97), a ubiquitously expressed ATPase with diverse cellular functions. By employing live-imaging methods in Drosophila larval axons and performing genetic interaction experiments, we discover that VCP regulates dynein-dependent axonal transport of mitochondria. Additionally, we investigate human pathogenic VCP mutations in our flies and discover pathogenic VCP mutations impact mitochondrial motility in a similar way as knocking down VCP. Finally, we demonstrate that enhancing Miro restores mitochondrial density loss in axons, rebalances directional mitochondrial motility, and improves ATP production. Additionally, we investigate the function of Leucine-Rich Repeat Kinase 2 (LRRK2) protein in mediating mitochondrial quality control. We identify a novel role for LRRK2 in promoting the removal of Miro from the OMM and facilitating mitophagy. We show this function of LRRK2 is disrupted by pathogenic mutations in Drosophila and patient derived cellular models of PD. Further, we demonstrate that impaired Miro degradation is a shared feature across several forms of PD. Finally, in our Drosophila model of LRRK2G2019S PD, we observed beneficial impacts in locomotive behavior and neuron survival by reducing Miro. This work highlights the link between mitochondrial motility and quality control, and the importance of these pathways in neuronal health and disease. We provide evidence to implicate impaired mitochondrial motility and quality control in the pathophysiology of VCP- relevant ALS and LRRK2- relevant Parkinson's Disease. Finally, our work suggests that Miro exists at the nexus of several important mitochondrial signaling pathways and may be a promising therapeutic target as we seek to develop treatments for diseases of the aging brain.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2020; ©2020 |
| Publication date | 2020; 2020 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Gonzalez, Ashley Elizabeth |
|---|---|
| Degree supervisor | Wang, Xinnan |
| Thesis advisor | Wang, Xinnan |
| Thesis advisor | Fuller, Margaret T, 1951- |
| Thesis advisor | Lu, Bingwei, 1968- |
| Thesis advisor | Reimer, Richard J |
| Degree committee member | Fuller, Margaret T, 1951- |
| Degree committee member | Lu, Bingwei, 1968- |
| Degree committee member | Reimer, Richard J |
| Associated with | Stanford University, Neurosciences Program. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Ashley Elizabeth Gonzalez. |
|---|---|
| Note | Submitted to the Neurosciences Program. |
| Thesis | Thesis Ph.D. Stanford University 2020. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2020 by Ashley Elizabeth Gonzalez
Also listed in
Loading usage metrics...