The genetic disease Hutchinson-Gilford Progeria Syndrome (HGPS) arises from a de novo single nucleotide mutation (1824CàT) in the LMNA gene. As a result, the mutated lamin A protein (progerin) remains farnesylated and permanently attached to the nuclear membrane. Progerin accumulates and deforms the nuclear membrane leading to an array of cellular abnormalities driving the cells to enter a state of permanent cell-cycle arrest early on in replicative age i.e. premature cellular senescence. Cellular senescence has been extensively studied as one of the contributing factors to aging in HGPS patients and other age-related diseases. There has also been evidence to show that aging is accompanied by epigenetic changes and that epigenetic manipulation can incite progeroid syndromes in mice. It has been found in this study that HGPS fibroblasts express distinctly lower levels of SIRT6, a member of the sirtuin family of NAD-dependent protein deacetylases/ADP-ribosyltransferases, than normal fibroblasts. Findings from this study demonstrate that overexpression of SIRT6 prevents a decrease in replicative capacity and the onset of premature senescence in HGPS fibroblasts. Thus, SIRT6 may have promising therapeutic implications for improving HGPS age-related pathologies.
| Identifer | oai:union.ndltd.org:vcu.edu/oai:scholarscompass.vcu.edu:etd-4237 |
| Date | 25 November 2013 |
| Creators | Endisha, Helal |
| Publisher | VCU Scholars Compass |
| Source Sets | Virginia Commonwealth University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | © The Author |
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