Mechanism of neurodegeneration in dystonia musculorum

描述（由申请人提供）：

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."