The Role of Mucolipin-1 in Microglia Function and Development in a Zebrafish Model of Mucolipidosis Type IV
Abstract/Contents
- Abstract
- Mucolipidosis type IV (MLIV) is an autosomal recessive lysosomal storage disease (LSD) characterized by delayed neurological development and severe reduction of psychomotor abilities. Mutations in MCOLN1, a lysosomal cation channel from the transient receptor potential (TRP) family, cause MLIV. Previous studies have successfully modeled MLIV in model organisms including fruit flies, mice, and zebrafish. Growing evidence suggests a link between aberrant lysosomal Ca2+ signaling and defective lysosome function. However, it still remains unclear how mutations in MCOLN1 lead to the debilitating neurodegenerative symptoms of MLIV. In this study, we used CRISPR-Cas9 gene editing to knockout the two mcoln1 genes present in Danio rerio (zebrafish). Our analysis suggests that mutations in MCOLN1 not only impair the function of lysosomes, but also disrupt microglia in the central nervous system (CNS). Microglia are specialized macrophages that monitor the health of the CNS, phagocytose cellular debris and pathogens, and prune weak synapses during neuronal development. Our functional mutational analysis revealed that mcoln1a-/- and mcoln1a-/-; mcoln1b-/- deficient mutants display abnormally enlarged microglial lysosomes, marked by fluorescent dye LysoTracker Red. Our results suggest that while mcoln1a is essential for microglia function, mcoln1b is largely dispensable. Overall, our analysis reveals a previously undescribed role of MCOLN1 in regulating microglia, which can provide a greater insight into the origins, neurological mechanisms, and progression of MLIV pathology.
Description
| Type of resource | text |
|---|---|
| Date created | April 24, 2019 |
Creators/Contributors
| Author | Gary, Ashlyn |
|---|
Subjects
| Subject | Mucolipidosis type IV |
|---|---|
| Subject | Zebrafish |
| Subject | Human Biology |
| Subject | Stanford University |
| Genre | Thesis |
Bibliographic information
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- User agrees that, where applicable, content will not be used to identify or to otherwise infringe the privacy or confidentiality rights of individuals. Content distributed via the Stanford Digital Repository may be subject to additional license and use restrictions applied by the depositor.
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- This work is licensed under a Creative Commons Attribution 3.0 Unported license (CC BY).
Preferred citation
- Preferred Citation
- Gary, Ashlyn. (2019). The Role of Mucolipin-1 in Microglia Function and Development in a Zebrafish Model of Mucolipidosis Type IV. Stanford Digital Repository. Available at: https://purl.stanford.edu/cj259fm1908
Collection
Stanford Theses and Dissertations
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- Contact
- ashlyng@stanford.edu
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