Interaction of polyglutamine fibrils with the mammalian cell surface
Abstract/Contents
- Abstract
- Neurodegeneration is currently as inexorable in its progression as it is devastating in its scope. Current therapies are largely ineffective, in large part because the etiology of disease is still undetermined. In all of these diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, the presence of a particular form of protein aggregate -- the amyloid fibril -- has led investigators to propose that this structure is a large facet of disease pathogenesis. Though this aggregate has been observed for centuries, how amyloid or amyloid precursors contribute to disease is still unknown. In mammalian prion diseases, amyloid is also central to pathology and transmission. In these cases, the amyloid fibril is an infectious unit, transmitted from individual to individual through consumption of contaminate brain or fecal matter or through contaminated surgical instruments. Recently, we and others have observed that amyloid fibrils derived from neurodegenerative-disease-related proteins like tau, [alpha]-synuclein, and polyglutamine can be transmitted from cell-to-cell in a manner similar to prion disease. These observations raise many questions regarding the mechanism of transmission and the contribution of this phenomenon to disease progression. This study analyzed the interaction of polyglutamine fibrils with the mammalian cell surface. We identified several factors that drastically influence the binding and internalization of polyglutamine fibrils. We show that fibrillar structure and the electrostatic composition of the fibril influences its binding to the cell surface. Furthermore, we demonstrate that polyglutamine fibrils bind to distinct binding sites on the surface, and that a particular class of sites seems to consist of proteins involved in cell adhesion. Finally, we describe a novel bioassay to determine genes involved in aggregate uptake on a genome-wide scale. The findings from this work increase our understanding of how this phenomenon occurs, and by extension will provide a foundation from which to understand whether the prion-like transmission of amyloid fibrils in neurodegeneration contributes to disease progression.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2012 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Trevino, Robert Sean |
|---|---|
| Associated with | Stanford University, Department of Biology. |
| Primary advisor | Kopito, Ron Rieger |
| Thesis advisor | Kopito, Ron Rieger |
| Thesis advisor | Cegelski, Lynette |
| Thesis advisor | Mudgett, Mary Beth, 1967- |
| Thesis advisor | Nelson, W. J. (W. James) |
| Advisor | Cegelski, Lynette |
| Advisor | Mudgett, Mary Beth, 1967- |
| Advisor | Nelson, W. J. (W. James) |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | R. Sean Trevino. |
|---|---|
| Note | Submitted to the Department of Biology. |
| Thesis | Ph.D. Stanford University 2012 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2012 by Robert Sean Trevino
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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