Mechanism of neurodegeneration in dystonia musculorum

描述（由申请人提供）： 突变小鼠肌张力障碍（dt）患有严重的遗传性感觉神经病变。小鼠在生命的第二周开始表现出肢体协调的进行性丧失。与野生型小鼠相比，dt小鼠的背根神经节体积小得多，感觉轴突内有细胞器和空泡积聚。充满神经丝、线粒体和膜结合致密体的局灶性轴突肿胀是这些小鼠病理学的标志。在突变小鼠中，细胞骨架的解体先于神经变性。在dt小鼠中突变的基因被称为肌张力障碍素，也被称为大疱性类天疱疮抗原1（BPAG 1）。BPAG 1是细胞骨架连接蛋白的斑蛋白家族的成员。Plakin家族成员具有特征性Plakin结构域，其可以与多种细胞粘附分子以及包含蛋白质家族（连环蛋白家族）的犰狳重复结构域的成员相互作用。此外，各种斑蛋白具有可以结合肌动蛋白微丝、微管和中间丝的结构域。在上皮细胞中，BPAG 1-e参与将角蛋白中间丝锚定到半桥粒。为什么半桥粒蛋白的缺失会引起神经元变性？为了研究这个问题，我们详细分析了BPAG 1基因座。我们发现，通过组织特异性剪接，它编码各种异构体与各种相互作用域的不同组合。在神经系统中有两种亚型表达：主要亚型BPAG 1-a和BPAG 1-n，其表达水平低于BPAG 1-a。BPAG 1-B是最大的同种型，在肌肉中高度表达。分别影响ABD和MTBD的选择性剪接的5'和3'末端可导致BPAG 1-a、BPAG 1-B和BPAG 1-n的另外的同种型。在这个提议中，我们将更详细地研究神经元亚型的功能，以了解为什么这种蛋白质的突变会导致神经元变性。该提案的重点是小鼠突变型肌张力障碍（dt）的原因，因此属于计划公告倡议PA- 02-156：“肌张力障碍的原因和机制研究”的范围。特别是，该提案符合PA针对的第二个研究领域的标准：“鉴定与肌张力障碍相关细胞因子（基因，蛋白质）相互作用的蛋白质并确定其协调功能。"

DESCRIPTION (provided by applicant): The mutant mouse dystonia musculorum (dt) suffers from a severe hereditary sensory neuropathy. The mice display progressive loss of limb coordination starting in the second week of life. Dorsal root ganglia of dt mice are considerably smaller in size than those of wild type mice with organelles and empty vacuoles accumulating within sensory axons. Focal axonal swellings filled with neurofilaments, mitochondria and membrane bound dense bodies are hallmarks of the pathology of these mice. The disorganization of the cytoskeleton precedes neurodegeneration in the mutant mice. The gene that is mutated in dt mice is called dystonin, and is also known as bullous pemphigoid antigen 1 (BPAG1). BPAG1 is a member of the plakin family of cytoskeletal linker proteins. Plakin family members have a characteristic plakin domain that can interact with a variety of cell adhesion molecules, as well as members of the armadillo-repeat domain containing protein family (catenin family). In addition, various plakins have domains that can bind to actin microfilaments, microtubules and intermediate filaments. In epithelial cells, BPAG1-e is involved in anchoring keratin intermediate filaments to the hemidesmosomes. Why does the deletion of a hemidesmosomal protein cause neuronal degeneration? To investigate this question, we have analyzed the BPAG1 locus in detail. We found that by tissue specific splicing, it encodes a variety of isoforms with different combinations of the various interacting domains. There are two isoforms expressed in the nervous system: the major isoform, BPAG1-a and BPAG1-n, which is expressed at lower levels than BPAG1-a. BPAG1-b is the largest isoform and is highly expressed in muscles. Alternatively spliced 5' and 3' ends that affect the ABD and MTBD respectively can lead to additional isoforms of BPAG1-a, BPAG1-b and BPAG1-n. In this proposal, we will study the function of the neuronal isoforms in more detail to understand why mutations of this protein result in neuronal degeneration. This proposal focuses on the cause for the mouse mutant dystonia musculorum (dt) and is therefore in the realm of the Program Announcement initiative PA- 02-156: "Studies into the causes and mechanisms of dystonia." In particular, the proposal meets the criteria of the second research area targeted by the PA: "Identification of proteins that interact with dystonia-related cellular factors (genes, proteins) and determination of their coordinated function."