Differential Protein Interactions in Hutchinson-Gilford Progeria Syndrome

 描述(由申请人提供)：核纤层(A-和B-型)形成一个网络，位于核内膜(INM)的下面并与其相互作用。核层和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定基因的调控都是重要的。鉴于核外周参与了多种细胞过程，核外周的蛋白质与包括早衰在内的一系列发育疾病有关也就不足为奇了。在经典的Hutchinson-Gilford Progeria综合征(HGPS)中，核内有一种异常的、未经加工的永久法尼化形式的Lamin A蛋白积聚，称为孕激素。有趣的是，在正常的衰老过程中，LMNA的另一个未经处理的变体被表达，表明节段性衰老疾病HGPS和正常衰老之间存在重叠。有人认为，孕激素整合到板层网络中会扰乱INM/板层的正常功能。与此相一致，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结构紊乱。HGPS细胞的其他已知标记包括RAN梯度倒置(对核输入很重要)、组蛋白H3K9和H3K27甲基化减少(异染色质标记)、LAP2β(一种内核膜蛋白)和Lamin B1丢失等。然而，很明显，表达孕激素的细胞对上述干扰表现出不同程度的敏感性。我们建议使用不同的易感细胞类型来识别特定的蛋白质配对，这些配对可能使不同的细胞和组织类型更容易或更抵抗孕激素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.