DOI

https://doi.org/10.25772/J4CY-YG75

Defense Date

2022

Document Type

Thesis

Degree Name

Master of Science

Department

Bioinformatics

First Advisor

Allison A. Johnson

Second Advisor

Derek C. Prosser

Third Advisor

Bret M. Boyd

Fourth Advisor

Maria Rivera

Fifth Advisor

Alaattin Kaya

Abstract

Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disease that causes loss of upper and/or lower motor neurons, and currently has no treatment or cure available. Over 90% of cases occur spontaneously with unknown causes, highlighting the complexity of the disease, and only 10% of cases are linked to heritable genetic mutations. Numerous ALS-linked genes are conserved through evolution, and model organisms may therefore provide opportunities to understand disease pathology at a molecular or cellular level, proving instrumental in identifying therapeutic targets. ALS subtype 8 (ALS8) is caused by an autosomal dominant P56S mutation in the VAPB gene that alters morphology and function of the endoplasmic reticulum (ER), leading to ER stress sensitivity. In a budding yeast (Saccharomyces cerevisiae) model of ALS8 that recapitulates these phenotypes, we identified Rab GTPases and their regulators involved in membrane traffic as a class of genes whose overexpression improved tolerance to ER stress. Yeast possesses 11 Rab genes, and while the majority of these are characterized and have clear homologs in mammals, the function of both YPT10 and YPT11 remain poorly understood. Notably, YPT10 was isolated as a possible suppressor of ALS8 phenotypes in the yeast model.

The goal of this study was to obtain genetic information about Ypt10 and Ypt11 function and phylogeny using bioinformatic approaches. By identifying the human homologs of yeast Rabs, we can potentially study their function, and identify targets for ALS treatments. This study narrowed down the potential human homologs for Ypt10 to Homo sapiens Rab20, Rab22a, and Rab31, as well as for Ypt11 to H. sapiens Rab34 and Rab36.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

12-14-2022

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