Regulation of lysosomes in myelination and microglia function
Abstract/Contents
- Abstract
- The central nervous system, composed of the brain and the spinal cord, is made up of two broad classes of cell types: neurons and glia. The interaction between glial cells and neurons is crucial for proper development and function of the nervous system. The first type of glial cells, macroglia, includes astrocytes and oligodendrocytes. Oligodendrocytes are the cells that form myelin, an evolutionary adaptation that allows rapid and efficient propagation of action potentials along axons. Diseases of myelin include multiple sclerosis, in which damage to the myelin sheath in the central nervous system disrupts flow of information between the brain and the body, often leading to debilitating symptoms. The second glia cell type, microglia, performs a variety of roles in the CNS including phagocytic clearance of dead neurons and debris. Microglia have been implicated in neurodegenerative diseases such as Alzheimer's Disease, which is characterized by memory loss, neuronal death and accumulation of abnormal amyloid plaques. By understanding the pathways that control microglia and oligodendrocyte development and function, novel therapies for CNS diseases may be developed by harnessing the capabilities of these cell types. In this dissertation, I focus on the roles of the Rag-Ragulator complex and other lysosomal-associated proteins in microglia and oligodendrocytes. In Chapter 2, I describe the identification of mutations that disrupt the Rag-Ragulator complex in a screen for myelin mutants. In mutants lacking RagA and Lamtor4, components of the Rag-Ragulator complex, myelinated axons are reduced compared to wildtype siblings, despite the presence of oligodendrocytes. The absence of Rag-Ragulator function prevents oligodendrocytes from maturing and ensheathing exons. These results point toward a key function of lysosomes in myelination. In Chapter 3, I describe the microglial function of the Rag-Ragulator complex. RagA and Lamtor4 mutants have a reduced number of microglia. The few microglia that are present have an expanded lysosomal compartment - yet are unable to properly clear debris that they have engulfed. In Chapter 4, I characterize Tcirg1b mutants, which exhibit a similar microglia phenotype to RagA mutants. Tcirg1b encodes a component of the vacuolar proton pump that acidifies the lysosome. Tcirg1b mutants have microglia that are engorged with undigested apoptotic neuronal debris. Together, this work defines new roles of lysosomal genes in oligodendrocytes and microglia, thereby highlighting the importance of lysosome function in different glial cell types.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2016 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Shen, Yanyin Kimberle |
|---|---|
| Associated with | Stanford University, Department of Developmental Biology. |
| Primary advisor | Talbot, William |
| Thesis advisor | Talbot, William |
| Thesis advisor | Bejerano, Gill, 1970- |
| Thesis advisor | Meyer, Tobias |
| Thesis advisor | Nusse, Roel, 1950- |
| Advisor | Bejerano, Gill, 1970- |
| Advisor | Meyer, Tobias |
| Advisor | Nusse, Roel, 1950- |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Yanyin Kimberle Shen. |
|---|---|
| Note | Submitted to the Department of Developmental Biology. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2016. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2016 by Yanyin Kimberle Shen
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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