Uncovering therapeutic strategies for TDP-43 proteinopathy
Abstract/Contents
- Abstract
- Amyotrophic Lateral Sclerosis (ALS) is a progressive paralytic disorder that leads to death usually within 3-5 years of onset. Mutations in over 40 genes have been associated with an increased risk of ALS, however, approximately 90% of patients have no family history of disease and no known disease-associated mutations. Despite this genetic diversity, one unifying characteristic of ALS is that 97% of patients have aggregates of the RNA-binding protein TDP-43 specifically in dying populations of neurons. Rare mutations in the gene encoding TDP-43 can cause ALS, suggesting that this protein has a pathogenic role in neurodegeneration. TDP-43 overexpression induces toxicity in a diverse range of model systems, including yeast, cultured human cells, and mouse neurons in vivo. Through unbiased, genome-wide screens, our lab previously discovered the yeast homolog of ataxin-2 is a dose-dependent modulator of toxicity induced by TDP-43 expression in yeast. To test whether this interaction holds true for mammalian neurons in vivo, I crossed ataxin-2 knockout mice to TDP-43 transgenic mice that overexpress human, wildtype TDP-43 specifically in neurons. I found that ataxin-2 reduction dramatically improves lifespan and ameliorates motor impairment in TDP-43 transgenic mice. We also demonstrated that an antisense oligonucleotide (ASO) drug that lowers ataxin-2 also improves lifespan and motor function. Additionally, ataxin-2 reduction decreased neuronal TDP-43 inclusions. These findings and additional work in cultured cells suggest that lowering ataxin-2 mitigates TDP-43 toxicity by reducing its propensity to aggregate. This work also suggests that ataxin-2 reduction could be an effective therapeutic intervention for ALS. To find novel modifiers of TDP-43 toxicity, I also performed a genome-wide CRISPRi screen in human cells. CRISPR technology has now made it possible to do genome-scale screens that were previously only feasible in yeast. We believe this screen will uncover bona fide modulators of TDP-43 proteinopathy that could inform new therapeutic strategies for ALS. I hypothesize that targeting the formation and physical properties of TDP-43 inclusions will be the key to protecting cells from TDP-43 toxicity.
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 | 2018; ©2018 |
| Publication date | 2018; 2018 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Becker, Lindsay Austin |
|---|---|
| Degree supervisor | Gitler, Aaron D |
| Thesis advisor | Gitler, Aaron D |
| Thesis advisor | Bassik, Michael |
| Thesis advisor | Reimer, Richard J |
| Thesis advisor | Wyss-Coray, Anton |
| Degree committee member | Bassik, Michael |
| Degree committee member | Reimer, Richard J |
| Degree committee member | Wyss-Coray, Anton |
| Associated with | Stanford University, Neurosciences Program. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Lindsay Austin Becker. |
|---|---|
| Note | Submitted to the Neurosciences Program. |
| Thesis | Thesis Ph.D. Stanford University 2018. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2018 by Lindsay Austin Becker
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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