POLYGLUTAMINE NEUROTOXICITY IN SBMA

X连锁脊髓和延髓肌萎缩症（SBMA），一种运动型 神经元疾病，是一个不断增长的名单所造成的疾病扩大 三核苷酸重复序列。 SBMA的突变是CAG扩大 在雄激素受体基因的第一个外显子中重复。 这个CAG重复 在受体蛋白的氨基端附近编码多聚谷氨酰胺区， 这类似于在其他蛋白质中发现的重复序列， 转录和发展的过程。 一个非常相似的重复变异 最近在亨廷顿氏病中被发现。 扩大 因此，CAG/多聚谷氨酰胺束可能是导致 神经退行性疾病 我们计划描述雄激素与 受体突变和运动神经元变性SBMA通过研究 突变雄激素受体在培养的神经元中的作用， 转基因小鼠 的普通版本和扩展版本构造 将在体外和体内测定雄激素受体的神经毒性。 由于雄激素受体蛋白的正常功能是作为一种 转录因子，疾病可能是由毒性获得引起的 受体蛋白的功能，可能的机制 神经毒性是通过改变一个或多个神经元的转录调节， 更多的目标基因 我们计划找出异常的靶基因， 由SBMA的扩展雄激素受体调节，并寻找 改变的受体对已知发挥作用的基因的特定影响 运动神经元存活率 我们希望我们的研究结果将增加对细胞的理解 运动神经元和类固醇激素受体的生物学。 这个项目 也应该阐明SBMA的发病机制，并可能导致有效的 治疗这种和其他遗传性退行性神经系统疾病 紊乱

X-linked spinal and bulbar muscular atrophy (SBMA), a form of motor neuron disease, is one of a growing list of disorders caused by expanded trinucleotide repeats. The mutation in SBMA is enlargement of a CAG repeat in the first exon of the androgen receptor gene. This CAG repeat encodes a polyglutamine tract near the amino end of the receptor protein, which is similar to repeats found in other proteins involved in control of transcription and development. A very similar repeat alteration has recently been found in Huntington's disease. Enlargement of CAG/polyglutamine tracts may thus be an important cause of neurodegenerative disease. We plan to characterize the causal connection between the androgen receptor mutations and the motor neuron degeneration of SBMA by studying the effects of the mutant androgen receptor in cultured neurons and transgenic mice. Constructs with normal and expanded versions of the androgen receptor will be assayed for neurotoxicity in vitro and in vivo. Since the normal function of the androgen receptor protein is as a transcription factor, and the disease is likely caused by a toxic gain of function of the receptor protein, the probable mechanism of neurotoxicity is through altered transcriptional regulation of one or more target genes. We plan to identify target genes that are aberrantly regulated by the expanded androgen receptor of SBMA and to look for specific effects of the altered receptor on genes known to play a role in motor neuron survival. We expect that our results will increase understanding of the cell biology of motor neurons and steroid hormone receptors. This project should also elucidate the pathogenesis of SBMA and may lead to effective treatment for this and other hereditary degenerative neurological disorders.