Identification of genetic modifiers of neurodegenerative diseases using CRISPR-Cas9 screens
Abstract/Contents
- Abstract
- Neurodegenerative diseases, such as Alzheimer's disease and Amyotrophic lateral sclerosis (ALS), pose one of the greatest risks to human health. Progress towards medical interventions is hindered by a lack of understanding of the underlying cellular and molecular causes of these diseases. In this work, I describe novel CRISPR-Cas9 screening approaches in human cells and primary neurons to understand neurodegenerative diseases. Through genome-wide CRISPR-Cas9 knockout screens in human cells, I describe hundreds of genetic modifiers of the toxic dipeptide repeat proteins (DPRs) associated with the C9orf72 repeat expansion, the most common cause of ALS. The genetic modifiers discovered in the human genome-wide screens are validated in the first reported CRISPR-Cas9 knockout screen in primary mouse neurons. Together, these screens revealed a novel therapeutic target for ALS, the ER resident protein TMX2. Additionally, I describe the development of a rapid genome-wide phenotypic screens for substrate specific regulators of phagocytosis, a process recently implicated in Alzheimer's disease. By conducting eight human genome-wide CRISPR knockout screens for regulators of phagocytosis of distinct substrates, I describe the discovery of a novel universal phagocytosis regulator, the previously-uncharacterized gene NHLRC2. Lastly I show that the previously-uncharacterized Alzheimer's disease-associated gene TM2D3 can selectively influence the phagocytosis of A aggregates. Together this work describes a novel approach to studying neurodegenerative diseases using human genome-wide knockout screens to reveal the cellular mechanisms and potential therapeutic targets for neurodegenerative diseases.
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 | Haney, Michael |
|---|---|
| Degree supervisor | Bassik, Michael |
| Thesis advisor | Bassik, Michael |
| Thesis advisor | Gitler, Aaron D |
| Thesis advisor | Li, Jin |
| Thesis advisor | Urban, Alexander E |
| Degree committee member | Gitler, Aaron D |
| Degree committee member | Li, Jin |
| Degree committee member | Urban, Alexander E |
| Associated with | Stanford University, Department of Genetics. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Michael Haney. |
|---|---|
| Note | Submitted to the Department of Genetics. |
| Thesis | Thesis Ph.D. Stanford University 2018. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2018 by Michael Seamus Haney
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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