Mechanisms of mutant huntingtin quality control and the impact on cellular proteostasis in Huntington's disease
Abstract/Contents
- Abstract
- Huntington's Disease is a neurodegenerative disorder characterized by a genetic mutation that expands a CAG trinucleotide repeat in exon 1 of the huntingtin gene resulting in a lengthened polyglutamine stretch. Importantly, the genetic neurodegenerative disorder Huntington's Disease shares key characteristics with other neurodegenerative diseases, including misfolded protein pathology and aberrant endolysosomal pathway function. While Huntington's Disease genetics pinpoints the underlying cause of disease, mechanisms of neurodegeneration and disease biology remain unclear. Many studies have highlighted a loss-of-function or gain-of-function caused by the mutant huntingtin protein, which has diverse cellular roles. However, rarely are both loss-of-function and gain-of-function aspects considered together. In this work, we aim to investigate altered huntingtin functions by comparing the in-cell protein-protein interactions of an exon 1 mutant huntingtin to exon 1 of the wild-type protein. We discover a gene set involved in the endolysosomal pathway that is highly specific to mutant huntingtin. We map endosomal interaction back to full-length huntingtin function, and show wild-type huntingtin and mutant huntingtin have fundamentally different interactions with endosomal membranes. These interactions highlight a novel VPS4 mediated protein quality control pathway we propose for regulating mutant huntingtin. Importantly, mutant huntingtin's altered endosomal interaction can be described by both a loss-of-wild-type-function and gain-of-mutant-function, which we correlate with widespread defects in endolysosomal pathway function. Ultimately, we propose a link between endolysosomal defects and the Huntington's Disease mutation, which provide mechanistic insight to disease relevant biology and inform potential therapeutic avenues.
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 | 2022; ©2022 |
| Publication date | 2022; 2022 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Masto, Vincent Bartholomew |
|---|---|
| Degree supervisor | Frydman, Judith |
| Thesis advisor | Frydman, Judith |
| Thesis advisor | Abu-Remaileh, Monther |
| Thesis advisor | Gozani, Or Pinchas |
| Thesis advisor | Ting, Alice Y |
| Degree committee member | Abu-Remaileh, Monther |
| Degree committee member | Gozani, Or Pinchas |
| Degree committee member | Ting, Alice Y |
| Associated with | Stanford University, Department of Biology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Vincent Masto. |
|---|---|
| Note | Submitted to the Department of Biology. |
| Thesis | Thesis Ph.D. Stanford University 2022. |
| Location | https://purl.stanford.edu/qy398zn6395 |
Access conditions
- Copyright
- © 2022 by Vincent Bartholomew Masto
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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