Studies Of Hereditary Neurological Disease

神经遗传学分支的目的是调查遗传性神经系统疾病的原因，目的是为这些疾病开发有效的治疗方法。特别感兴趣的研究领域包括多聚谷氨酰胺扩增疾病（亨廷顿病、肯尼迪病和脊髓小脑性共济失调）、脊髓性肌萎缩、夏科-马里-图思病、肌营养不良、遗传性运动神经元病和弗里德赖希共济失调。在细胞培养和其他模型系统中研究疾病机制。遗传外展计划允许识别和描述遗传性神经系统疾病的患者和家庭。艾地苯醌治疗弗里德赖希共济失调的试验最近完成，度他雄胺治疗肯尼迪病的试验正在进行中。预计将进行进一步的治疗试验。在过去一年中取得的具体研究成果包括：（1）我们进一步表征了细胞培养和果蝇多聚谷氨酰胺病模型中神经元死亡的机制，研究了profilin的作用和IGF-1的有益作用。(2)我们进一步描述了常染色体显性运动神经元病中转运蛋白dynactin突变的生化效应、临床和病理表现。(3)我们进一步描述了甘氨酰-tRNA合成酶突变引起的运动神经元病的表现。(4)我们报告了在转基因小鼠中对X连锁腓骨肌萎缩症的进一步研究。(5)我们进一步表征了组蛋白乙酰化和组蛋白去乙酰化酶抑制剂对SMN表达的影响，SMN是脊髓性肌萎缩症中突变的基因，我们在该疾病的小鼠模型中证明了治疗反应。(6)我们完成了艾地苯醌治疗弗里德赖希共济失调的2期研究，比较了高剂量、低剂量和安慰剂治疗。(7)我们开始了一项安慰剂对照的2期研究，研究度他雄胺治疗肯尼迪病。

The purpose of the Neurogenetics Branch is to investigate the causes of hereditary neurological diseases, with the goal of developing effective treatments for these disorders. Particular areas of research interest include the polyglutamine expansion diseases (Huntington's disease, Kennedy's disease, and spinocerebellar ataxia), spinal muscular atrophy, Charcot-Marie-Tooth disease, muscular dystrophy, hereditary motor neuron disease, and Friedreich's ataxia. The disease mechanisms are studied in cell culture and other model systems. A genetic outreach program allows the identification and characterization of patients and families with hereditary neurological diseases. A trial of idebenone treatment in Friedreich's ataxia was recently completed, and a trial of dutasteride treatment for Kennedy's disease is in progress. Further therapeutic trials are anticipated. Specific research accomplishments in the past year include the following: (1) We further characterized the mechanism of neuronal death in cell culture and Drosophila models of polyglutamine disease, investigating the role of profilin and the beneficial effects of IGF-1. (2) We further characterized the biochemical effects and clinical and pathological manifestations of a mutation in the transport protein dynactin in an autosomal dominant form of motor neuron disease. (3) We further characterized the manifestations of motor neuronopathy due to mutations in glycyl-tRNA synthetase. (4) We reported further studies of X-linked Charcot-Marie-Tooth disease in transgenic mice. (5) We further characterized the effects of histone acetylation and histone deacetylase inhibitors on the expression of SMN, the gene that is mutated in spinal muscular atrophy, and we demonstrated a therapeutic response in a mouse model of the disease. (6) We completed a phase 2 study of idebenone treatment in Friedreich's ataxia comparing high dose, low dose, and placebo treatment. (7) We started a placebo-controled phase 2 study of dutasteride treatment in Kennedy's disease.