POLYGLUTAMINE NEUROTOXICITY IN SBMA

X连锁脊髓和延髓肌萎缩症(SBMA)，运动的一种形式 神经元疾病，是由扩张性疾病引起的越来越多的疾病之一 三核苷酸重复。SBMA中的突变是CAG的扩大 在雄激素受体基因的第一个外显子重复。此CAG重复 在受体蛋白的氨基末端附近编码一条多谷氨酰胺链， 这与在其他参与控制的蛋白质中发现的重复序列相似 转录和发育。一个非常类似的重复改变有 最近在亨廷顿氏症中被发现。扩大业务范围 因此，CAG/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之间的因果关系 受体突变与SBMA运动神经元变性的研究 突变型雄激素受体对培养神经元的影响 转基因小鼠。的常规版本和扩展版本的构造 雄激素受体将在体外和体内进行神经毒性检测。 由于雄激素受体蛋白的正常功能是 转录因子，这种疾病可能是由一种有毒的获得物引起的 受体蛋白的功能，可能的机制是 神经毒性是通过改变一个或一个或多个基因的转录调控 更多的靶基因。我们计划找出异常的靶基因 受SBMA扩张型雄激素受体的调节并寻找 改变的受体对已知发挥作用的基因的特异性影响 运动神经元的存活。 我们希望我们的结果将增加对细胞的了解 运动神经元和类固醇激素受体的生物学。这个项目 也应阐明SBMA的发病机制，并可能导致有效 本病及其他遗传性退行性神经病的治疗 精神错乱。

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.