Year: 2016
Type: dissertation
Abstract: The polyglutamine expansion of the human gene ATXN2 is associated with neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS) and Spinocerebellar Ataxia type 2 (SCA2). Work in our lab demonstrated that deletion of the Saccharomyces cerevisiae ATXN2 orthologue Pbp1 results in the accumulation of RNA-DNA hybrids. Here I demonstrate that hybrid accumulation in pbp1Î cells triggers aberrant recombination within the ribosomal DNA (rDNA) repeats and shortening of replicative lifespan. These deleterious phenotypes can be rescued by caloric restriction. To better model disease I created a yeast genetic model of human ATXN2-linked diseases by generating cells expressing polyglutamine-expanded Pbp1. These cells also had shorter replicative lifespan. However, hybrid accumulation or aberrant recombination within the rDNA repeats was unaffected. Instead, these strains demonstrate gross chromosomal rearrangement more substantial than those observed in pbp1Î cells suggesting that replicative lifespan is impacted by distinctive mechanisms in strains lacking Pbp1 or expressing polyglutamine-expanded Pbp1.
Source: TSpace (University of Toronto)
Author: Kirk Matthew James Szafranski
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3088127162