Studies Of Hereditary Neurological Disease

神经遗传学分部的目的是调查遗传性神经疾病的原因，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聚谷氨酰胺扩张性疾病(亨廷顿病、肯尼迪病和脊髓小脑性共济失调)、脊髓性肌萎缩症、夏科-玛丽-牙病、肌营养不良、遗传性运动神经元病和弗里德里希共济失调。在细胞培养和其他模型系统中对疾病机制进行了研究。遗传外展计划允许识别和描述患有遗传性神经疾病的患者和家庭的特征。艾地苯酮治疗Friedreich共济失调的试验正在进行中。预计还会有更多的治疗试验。过去一年的具体研究成果包括：(1)我们进一步研究了细胞培养中神经元死亡的机制和多谷氨酰胺病的果蝇模型。(2)我们完成了体外药物筛选，确定了减轻细胞培养中多聚谷氨酰胺毒性的治疗方法。(3)我们帮助确定了一种常染色体显性遗传性运动神经病(ALS4)的遗传缺陷。(4)我们帮助确定了遗传性轴索神经病(CMT2D)的致病基因。(5)我们研究了一种常染色体显性遗传性运动神经元病中转运蛋白dynactin突变的影响。(6)我们完成了艾地苯酮治疗Friedreich‘s共济失调患者的1a期剂量递增和耐受性研究，并开始了长期高剂量耐受性研究(1b期)。(7)我们发现了一种能增加脊髓性肌萎缩症患者细胞中缺陷蛋白SMN水平的药物(丙戊酸)，并研究了其他组蛋白去乙酰酶抑制剂对SMN基因表达的影响。

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 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. (2) We completed an in vitro drug screen and identified treatments that mitigate polyglutamine toxicity in cell culture. (3) We helped to identify the genetic defect responsible for an autosomal dominant form of motor neuronopathy (ALS4). (4) We helped in the characterization of the gene responsible for hereditary axonal neuropathy (CMT2D). (5) We characterized the effects of a mutation in the transport protein dynactin in an autosomal dominant form of motor neuron disease. (6) We completed a phase 1a dose escalation and tolerability study of idebenone therapy in patients with Friedreich's ataxia and began a chronic high dose tolerability study (phase 1b). (7) We identified an agent (valproic acid) that increases levels of the deficient protein SMN in cells from patients with spinal muscular atrophy and characterized the effect of other histone deacetylase inhibitors on SMN gene experssion.