Profilin 1, stress granules, and ALS pathogenesis
Abstract/Contents
- Abstract
- Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is the most common adult-onset motor neuron disease. Upper and lower motor neurons mysteriously begin to degenerate in ALS patients resulting in muscle weakness rapidly progressing to paralysis and death within only a few years. There has been an explosion in the knowledge of the genetic causes of ALS in the last decade and pathogenic mechanisms are emerging (Chapter 1). In this dissertation I have attempted to contribute to the understanding of ALS mechanisms with the ultimate goal of helping to halt or slow the disease. With experiments in yeast and mammalian cells, I have discovered a novel role for the ALS-linked actin-binding protein profilin 1 in cellular stress granules and showed that ALS- linked profilin 1 mutant proteins have altered stress granule dynamics (Chapter 2). Profilin 1 now joins a growing list of ALS-linked proteins that transit into stress granules. Interestingly, many stress granule proteins are also observed in the neuropathology of ALS motor neurons. Stress granules have been proposed to act as crucibles of ALS pathogenesis, but their composition has been notably difficult to fully identify. Here I present a comprehensive literature review of all reports that have discovered stress granule-associated proteins (Appendix) and my progress towards the development of an unbiased method to determine the proteome of stress granules using an enzymatic tagging strategy in live human cells (Chapter 3). Finally, noncoding DNA repeat expansions in the C9orf72 gene were recently identified as the largest known cause of ALS to date. Here I present negative results from a genetic analysis in several hundred ALS patients and healthy controls of noncoding repetitive DNA regions in candidate genes known to cause other neurological and neuromuscular diseases. The lack of association with ALS in these genes suggests that they do not contribute to ALS pathogenesis (Chapter 4). Together, these experiments and results support the hypothesis that stress granules are intimately linked to ALS pathogenesis and provide a path forward towards further understanding of the role of stress granule biology in the normal cellular stress response and how their dysfunction might contribute to disease.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2015 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Figley, Matthew |
|---|---|
| Associated with | Stanford University, Neurosciences Program. |
| Primary advisor | Gitler, Aaron D |
| Thesis advisor | Gitler, Aaron D |
| Thesis advisor | Reimer, Richard J |
| Thesis advisor | Wang, Xinnan |
| Thesis advisor | Wyss-Coray, Anton |
| Advisor | Reimer, Richard J |
| Advisor | Wang, Xinnan |
| Advisor | Wyss-Coray, Anton |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Matthew Figley. |
|---|---|
| Note | Submitted to the Program in Neurosciences. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2015. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2015 by Matthew David Figley
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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