Differential Protein Interactions in Hutchinson-Gilford Progeria Syndrome

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 DESCRIPTION (provided by applicant): The nuclear lamins (A- and B-type) form a meshwork underlying, and interacting with proteins of the inner nuclear membrane (INM). The proteins of the nuclear lamina and INM are important for the 3D structure of the nucleus, scaffolding of the genome and regulation of key cell type specific genes. Given the involvement of the nuclear periphery in a multitude of cellular processes, it is perhaps not surprising that proteins at the nuclear periphery have been implicated in a range of developmental diseases, including premature aging. In classical Hutchinson-Gilford Progeria Syndrome (HGPS) there is an accumulation of an aberrant and unprocessed permanently farnesylated form of the lamin A protein, called progerin, in the nucleus. Intriguingly, during the normal aging process another unprocessed variant of LMNA is expressed, indicating overlap between the segmental aging disease HGPS and normal aging. It is thought that integration of progerin into the lamina meshwork perturbs the normal function of the INM/lamina. In agreement with this, features of cells carrying aberrant variants of LMNA found in HGPS include nuclear morphological abnormalities and disorganization of heterochromatin. Other documented markers of HGPS cells include inversion of the Ran gradient (important for nuclear import), decrease in histone H3K9 and H3K27 methylation (markers of heterochromatin), loss of Lap2β (an inner nuclear membrane protein) and Lamin B1, among others. However, it is clear that cells expressing progerin show different levels of susceptibility to the above-noted disruptions. We propose to use differentially susceptible cell types to identify specific protein partners that may render different cell and tissue types more susceptible or resistant to the deleterious effects of progeri protein expression.