Graduation Term

2023

Degree Name

Master of Science (MS)

Department

School of Biological Sciences

Committee Chair

Alysia Vrailas-Mortimer

Committee Member

Wolfgang Stein

Abstract

Charcot-Marie-Tooth Disease (CMT) is a progressive neuropathology caused by the deterioration of neuronal function of the peripheral motor and sensory nervous systems. Motor symptoms include tripping, ankle twisting, and clumsiness, while sensory symptoms include sensations such as pins and needles and burning pain. Though mutations in a variety of genes can give rise to CMT, several of the genes are tRNA-synthetases. We have recently found that the p38 MAPK (p38Kb), a kinase involved in aging and age-dependent locomotor deficits, regulates the levels of several tRNA-synthetase proteins during aging. p38Kb interacts with the Chaperone-Assisted Selective Autophagy (CASA) complex to mediate the degradation of misfolded or nonfunctional proteins, a process that could also contribute to clearing tRNA-synthetase proteins that are damaged from aging. Failure to clear damaged proteins may result in disease symptoms or worsening of symptoms. I hypothesize that p38Kb-mediated regulation of tRNA synthetase degradation is crucial for maintaining proper neuromuscular function. Utilizing a well-established genetic model in Drosophila melanogaster, I further investigated whether there is a relationship between p38Kb and the tRNA synthetase GARS in the context of protein homeostasis. I explored their individual and combined contributions to CMT-like phenotypes in the context of CMT2D. This work has helped shed light on a p38Kb-GARS relationship, as well as the pathogenesis of CMT2D.

Access Type

Thesis-Open Access

DOI

https://doi.org/10.30707/ETD2023.20231004061829208270.999961

Download

Share

COinS