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。遗传外展计划旨在识别和表征遗传性神经系统疾病患者和家庭。艾地苯醌治疗弗里德赖希共济失调的试验正在进行中。预计将进行进一步的治疗试验。具体研究成果包括：（1）在细胞培养和果蝇多聚谷氨酰胺病模型中，我们进一步表征了神经元死亡的机制。(2)我们已经完成了体外药物筛选，并确定了减轻细胞培养中聚谷氨酰胺毒性的治疗方法。(3)我们已经帮助缩小了对定位于9号染色体的常染色体显性运动神经元病遗传缺陷的搜索范围。(4)我们帮助鉴定了遗传性轴索神经病（CMT 2D）的基因。(5)我们确定了常染色体显性运动神经元病的基因。(6)我们在弗里德赖希共济失调患者中进行了艾地苯醌治疗的1期剂量递增和耐受性研究。(7)我们已经确定了一种药物（丙戊酸盐），可增加脊髓性肌萎缩症患者细胞中缺乏蛋白SMN的水平。

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 is intended to identify and characterize patients and families with hereditary neurological diseases. A trial of idebenone treatment in Friedreich's ataxia is in progress. Further therapeutic trials are anticipated. Specific research accomplishments in the past year include the following: (1) We have further characterized the mechanism of neuronal death in cell culture and Drosophila models of polyglutamine disease. (2) We have completed an in vitro drug screen and identified treatments that mitigate polyglutamine toxicity in cell culture. (3) We have helped to narrow the search for the genetic defect responsible for an autosomal dominant form of motor neuronopathy mapped to chromosome 9. (4) We have helped in the identification of the gene responsible for hereditary axonal neuropathy (CMT2D). (5) We identified the gene for an autosomal dominant form of motor neuron disease. (6) We have carried out a phase 1 dose escalation and tolerability study of idebenone therapy in patients with Friedreich's ataxia. (7) We have identified an agent (valproate) that increases levels of the deficient protein SMN in cells from patients with spinal muscular atrophy.