Differential Protein Interactions in Hutchinson-Gilford Progeria Syndrome

 描述（由申请人提供）：核纤层蛋白（A型和B型）形成核内膜（INM）蛋白的底层网络，并与之相互作用。核纤层和INM的蛋白质对于核的3D结构、基因组的支架和关键细胞类型特异性基因的调节是重要的。鉴于核外围参与了许多细胞过程，核外围的蛋白质与一系列发育疾病（包括过早衰老）有关可能并不奇怪。在经典的Hutchinson-Gilford早老综合征（HGPS）中，核纤层蛋白A蛋白的异常和未加工的永久法尼基化形式（称为早老蛋白）在细胞核中积累。有趣的是，在正常衰老过程中，LMNA的另一种未加工变体表达，表明节段性衰老疾病HGPS和正常衰老之间存在重叠。据认为，早老蛋白整合到板层网络中扰乱了INM/板层的正常功能。与此一致，在HGPS中发现的携带LMNA异常变体的细胞的特征包括核形态异常和异染色质的解体。HGPS细胞的其他记录的标志物包括Ran梯度的反转（对核输入很重要），组蛋白H3 K9和H3 K27甲基化（异染色质的标志物）的减少，Lap 2 β（一种内核膜蛋白）和核纤层蛋白B1的丢失等。然而，很明显，表达早老蛋白的细胞显示出对上述破坏的不同水平的易感性。我们建议使用不同的易感细胞类型，以确定特定的蛋白质合作伙伴，可能使不同的细胞和组织类型更容易或抵抗progeri蛋白表达的有害影响。

 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.