SUN-nesprin complexes in human laminopathies

描述(申请人提供)：A型和B型核纤层是蛋白质中间丝家族的成员，代表核膜(NE)的重要结构元素。去甲肾上腺素在细胞核和细胞质之间起着选择性屏障的作用。A型lamin基因LMNA的突变与多种人类疾病有关，这些疾病通常被称为椎板病，包括常染色体显性遗传性Emery-Dreifuss肌营养不良症(AD-EDMD)、扩张型心肌病、Dunnigan型家族性脂肪营养不良症和Hutchinson Gilford早老症综合征。一种X连锁的EDMD是由另一种NE蛋白Emerin的缺陷引起的。Emerin是内核膜的一种完整蛋白，与A-型层蛋白有关。A-型层蛋白和胞外蛋白都被广泛表达。因此，令人费解的是，为什么这些蛋白质的缺陷会导致如此令人困惑的一系列疾病。最近的研究结果表明，A型板层和Emerin的疾病相关缺陷与细胞骨架的改变有关，导致成纤维细胞细胞质的机械弹性降低。我们最近定义了一个复合体，它由SUN和Nesprin蛋白家族的成员组成，作为NE和细胞骨架之间的纽带。我们称之为LINC复合体(核骨架和细胞骨架的连接物)。LINC复合体是已知的A型板层和细胞骨架之间唯一的连接。我们假设是LINC复合体介导了与A-型层粘连蛋白和Emerin基因突变相关的细胞骨架变化。通过这种方式，LINC复合体可能在EDMD和其他椎板病变的病因学中起关键作用。通过更好地了解参与这些疾病发展的分子相互作用，我们可能处于更好的地位，以设计基于药物或基因的新治疗策略。 公共卫生相关性：A型板层是核膜(NE)的重要组成部分。A型层蛋白基因(LMNA)的缺陷与多种人类疾病或椎板病有关，包括肌营养不良症、脂肪营养不良症和早衰症。这项建议的目的是确定层蛋白缺陷导致这种疾病的机制，并测试NE的SUN和NESPrin蛋白是这些层蛋白相关病理的中介这一概念。

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.