Beclin-1 mediated protein sorting in neurodegeneration
Abstract/Contents
- Abstract
- Protein sorting coordinates membrane dynamics with the clustering and isolation of proteins into discrete membrane domains. Proper protein sorting not only mediates intracellular homeostasis, for example, through the delivery of hydrolase enzymes to the lysosome or through degradation of long-lived proteins in autophagy. It also facilitates the communication between a cell and its environment (the extracellular milieu or neighboring cells) by regulating both ligand secretion as well as the availability of receptors at the plasma membrane by balancing receptor degradation with receptor recycling. Disruption of protein sorting pathways can therefore interfere with intracellular processes and prevent the interactions between cells necessary for the maintenance of tissue homeostasis. The nervous system, in particular, is sensitive to disruption of protein sorting pathways, as evidenced by the growing number of reports linking polymorphisms in protein sorting machinery to neurological disease, such as Alzheimer's Disease (AD). It is therefore necessary to elucidate the mechanisms controlling protein sorting so that we may better understand the normal biology underlying these processes and the consequences of their disruption in pathogenesis. Previous work has established that levels of beclin 1, a protein that functions in multiple membrane trafficking pathways, are decreased in the brains of Alzheimer's Disease patients. We show that, in addition to it's well-known function in regulating autophagy, beclin 1 regulates receptor recycling in two systems relevant to neurodegeneration: phagocytosis in microglia and TGF-[beta] signaling in neurons. We use immunocytochemistry, confocal microscopy, and live-cell imaging to demonstrate beclin 1 regulates receptor recycling through production of phosphatidylinositol-3-phosphate at vesicle membranes and recruitment of the retromer complex. We also use a combination of biochemical techniques, flow cytometry, and immunohistochemistry to show the functional consequence of disrupted receptor recycling in phagocytosis and the TGF-[beta] signaling pathway using both in vitro and in vivo models. In light of our findings, we discuss the implications of impaired beclin 1-mediated protein sorting in neurological 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 | O'Brien, Caitlin E |
|---|---|
| Associated with | Stanford University, Department of Biology. |
| Primary advisor | Wyss-Coray, Anton |
| Thesis advisor | Wyss-Coray, Anton |
| Thesis advisor | Nelson, William |
| Thesis advisor | Reimer, Richard J |
| Thesis advisor | Yang, Yanmin, Ph. D |
| Advisor | Nelson, William |
| Advisor | Reimer, Richard J |
| Advisor | Yang, Yanmin, Ph. D |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Caitlin E. O'Brien. |
|---|---|
| Note | Submitted to the Department of Biology. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2015. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2015 by Caitlin Elizabeth O'Brien
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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