Developing and Applying a Yeast Model of Hutchinson-Gilford Progeria Syndrome
Date
2024-01-12
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
0009-0005-1918-1678
Type
Thesis
Degree Level
Masters
Abstract
The human premature aging disorder Hutchinson-Gilford progeria syndrome can, by virtue of its single molecular cause, be introduced to other living systems which allows for a more controlled and nuanced study of the disease. We have applied this philosophy to the study of aging in yeast (Saccharomyces cerevisiae) and generated a model system of premature aging which captures several of the major molecular phenotypes of Hutchinson-Gilford progeria syndrome. Our system is based on a galactose inducible pYES plasmid vector system that is readily maintained in yeast under selection and that expresses the disease-causing progerin protein N terminally tagged with EGFP. We successfully applied the yeast model of progeria towards exploring interactions and influences between core cellular processes and the severity of the Hutchinson-Gilford rapid aging phenotype. This initially involved inducing Hutchinson-Gilford progeria syndrome in mutant yeast strains with single non-essential gene deletions and screening for phenotype severity. This screening further reinforced confidence in our yeast model of progeria by implicating several processes, including those of genomic stability and mitochondrial function and organization, which were previously known to be influenced by Hutchinson-Gilford type premature aging. As such, we proceeded to apply the yeast model of progeria towards the study of the syndrome. Deletions of individual subunits of the Chromatin Assembly Factor 1 replication-dependent histone assembly complex were found to apparently reduce the fitness-impairment effect of progerin expression in yeast and so represented promising ground for in-depth assessment. Our work suggests that activity of Chromatin Assembly Factor 1 influences the severity of the Hutchinson-Gilford rapid aging phenotype and represents a promising target for future studies.
Description
Keywords
Yeast, Aging, Premature Aging, HGPS, Hutchinson-Gilford progeria syndrome, Chromatin assembly factor 1, Model system of disease
Citation
Degree
Master of Science (M.Sc.)
Department
Biochemistry
Program
Biochemistry