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Access Type
WSU Access
Date of Award
January 2022
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Anatomy and Cell Biology
First Advisor
Ryan Thummel
Abstract
Genetic leukoencephalopathies (gLE) are a group of white matter abnormalities that affect the nervous system, resulting in diverse infantile on-set clinical pathologies. The neurological abnormalities are progressive in nature and include motor abnormalities, systemic and sensory defects, and cognitive impairment. A novel founder mutation in the endolysosomal trafficking protein VPS11 was identified to be associated with patients from the Ashkenazi Jewish community, manifesting gLE-like symptoms. However, the underlying role of VPS11 in the nervous system is unknown. This dissertation aims to characterize myelin and vision defects associated with abnormalities in Vps11 and to establish a zebrafish model to study the resulting physiological and behavioral consequences. First, we showed strong expression of Vps11 oligodendrocytes and myelin using a mouse model, providing the first report of Vps11 localization at the neuro-axon interface of the mammalian nervous system. Next, we used behavior analysis on the hypomyelinated vps11(plt) and vps11(-/-) zebrafish mutant lines to show progressive loss of sensorimotor responses to visual and non-acoustic stimuli, establishing it a vertebrate model to study Vps11-associate gLE. Furthermore, as Vps11 functions with other c-Vps proteins, we characterized the vps16 zebrafish model. We found that these animals show systemic, neurological, and behavioral abnormalities. The Vps16-asscoiated pathologies are comparable with multiple neurological disorders including gLE, indicating a necessity for a better understanding of the role of Vps16 in the nervous system. Finally, in an early-stage pharmacological screen using zebrafish vps11 mutants, we utilized two pro-myelinating drugs to show that the chemicals were unable to rescue the loss of sensorimotor behavioral response of the hypomyelinated mutants. Collectively, these studies have provided significant insight into the expression of and function of Vps11 in the nervous system and its role in human gLE. This will enable future endeavors exploring potential therapeutics.
Recommended Citation
Banerjee, Shreya, "Myelin And Vision Defects Associated With A Novel Mutation In The Endolysosomal Protein Vps11" (2022). Wayne State University Dissertations. 3751.
https://digitalcommons.wayne.edu/oa_dissertations/3751