SUN-nesprin complexes in human laminopathies

描述（由申请人提供）：A型和B型核纤层蛋白是蛋白质中间丝家族的成员，代表核膜（NE）的重要结构元件。NE作为细胞核和细胞质之间的选择性屏障发挥作用。A型核纤层蛋白基因LMNA中的突变与多种人类疾病（通常称为核纤层蛋白病）相关，所述人类疾病包括常染色体显性埃默里-德赖富斯肌营养不良（AD-EDMD）、扩张型心肌病、邓尼根型家族性脂肪营养不良和哈钦森吉尔福德早老综合征。EDMD的X连锁形式是由另一种NE蛋白质Emerin的缺陷引起的。Emerin是内核膜的一种整合蛋白，与A型核纤层蛋白相关。A型核纤层蛋白和emerin都广泛表达。因此，为什么这些蛋白质的缺陷会引起如此令人困惑的疾病，这是令人费解的。最近的结果表明，A型核纤层蛋白和突蛋白两者中的疾病相关缺陷与细胞骨架变化相关，导致成纤维细胞中细胞质的机械弹性降低。我们最近定义了一个复杂的SUN和nesprin蛋白家族的成员组成的NE和cytokeleton之间的联系的功能。我们称之为LINC复合物（核骨架和细胞骨架的连接物）。LINC复合物是A型核纤层蛋白和细胞骨架之间唯一已知的连接。我们推测，这是LINC复合物介导的细胞骨架的变化与突变的A型核纤层蛋白和emerin基因。以这种方式，LINC复合物可能在EDMD和其他层粘连蛋白病的病因学中起关键作用。通过对这些疾病发展中所涉及的分子相互作用的更好理解，我们可以更好地设计新的基于药物或基因的治疗策略。 公共卫生相关性：A型核纤层蛋白是核膜（NE）的重要成分。A型核纤层蛋白基因（LMNA）的缺陷与多种人类疾病或核纤层蛋白病有关，包括肌营养不良、脂肪营养不良和早衰症。本提案的目的是确定核纤层蛋白缺陷可能导致此类疾病的机制，并测试NE的SUN和nesprin蛋白是这些核纤层蛋白相关病理的介体的概念。

DESCRIPTION (provided by applicant): The A- and B-type nuclear lamins are members of the intermediate filament family of proteins and represent important structural elements of the nuclear envelope (NE). The NE functions as a selective barrier between the nucleus and cytoplasm. Mutations in the A-type lamin gene, LMNA, have been linked to a variety of human disorders, often referred to as laminopathies, that include autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD), dilated cardiomyopathy, Dunnigan type familial lipodystrophy and Hutchinson Gilford progeria syndrome. An X-linked form of EDMD is caused by defects in another NE protein, emerin. Emerin is an integral protein of the inner nuclear membrane and is associated with the A-type lamins. Both the A-type lamins and emerin are widely expressed. It is therefore puzzling why defects in these proteins should give rise to such a bewildering array of diseases. Recent results have shown that disease- linked defects in both A-type lamins and emerin are associated with cytoskeletal changes resulting in reduced mechanical resilience of the cytoplasm in fibroblasts. We have recently defined a complex consisting of members of both the SUN and nesprin protein families that functions as a link between the NE and the cytokeleton. We have termed this the LINC complex (LInker of Nucleoskeleton and Cytoskeleton). The LINC complex is the only known connection between the A-type lamins and the cytoskeleton. We hypothesize that it is the LINC complex that mediates the cytoskeletal changes associated with mutation of the A-type lamin and emerin genes. In this way the LINC complex might have a key role in the etiology of EDMD and other laminopathies. By gaining an improved understanding of the molecular interactions involved in the development of these disorders we may be in a better position to devise novel drug- or gene-based therapeutic strategies. PUBLIC HEALTH RELEVANCE: The A-type lamins are important components of he nuclear envelope (NE). Defects in the A-type lamin gene (LMNA) are linked to a variety of human diseases or laminopathies, which include muscular dystrophy, lipodystrophy and progeria. The goal of this proposal is to determine the mechanism by which lamin defects can cause such disorders and to test the notion that SUN and nesprin proteins of the NE are mediators of these lamin-linked pathologies.