Cellular Defects in Hutchinson-Gilford Progeria Syndrome

The Hutchinson-Gilford Progeria Syndrome(HGPS) is a premature aging syndrome in children that is caused by the disruption of the nuclear lamina owing to the expression of Progerin, a mutant form of the Lamin A protein. This leads to altered physical properties of the lamina causing changes in nuclear morphology. Additionally there are structural alterations in chromatin along with global changes in gene expression patterns. However the intermediate mechanisms linking lamina perturbation to the above phenotypes have been a subject of investigation. The Ran protein gradient and nuclear SUMOylation are two fundamentally important mediators of normal nuclear function and both are disrupted in HGPS. In the first part of this dissertation, I show that the mislocalization of SUMO E2 Ubc9 in HGPS drives the loss of nuclear SUMOylation, which in turn disrupts the Ran gradient. In the second part of this dissertation I demonstrate that a loss of the Ran gradient can also cause defective nuclear import of Ubc9, thus pointing to a mutually regulatory mode of function between the Ran and SUMOylation systems. In addition to causing defective Ubc9 import, disruption of the Ran gradient induces oxidative stress, the latter being a part of a newly emerging concept in HGPS. The resultant increase in ROS could in principle feed back into the Ran gradient generating machinery and worsen the Ran gradient. This study identifies the Ran gradient disruption as an early event in HGPS, which by affecting two diverse pathways namely redox balance and nuclear SUMOylation, serves the role of an important mediator of the progressive cellular changes in HGPS.