NAD, PGC-1alpha and SIRT3 as Therapeutics Targets for Huntington's Disease

 描述（由申请人提供）：亨廷顿病（HD）是一种常染色体显性进行性神经退行性疾病，可导致认知和运动缺陷以及严重残疾。该疾病是由不稳定的CAG重复扩增引起的，其导致蛋白亨廷顿内的多聚谷氨酰胺延伸。突变亨廷顿蛋白的毒性作用导致转录失调以及线粒体功能障碍和氧化损伤。PGC-1 α是一种控制线粒体生物合成和抗氧化酶表达的转录辅激活因子，缺乏PGC-1 α。还有SIRT 3的缺陷，SIRT 3是一种蛋白质脱乙酰酶，其在线粒体内的表达依赖于PGC-1 α。我们建议验证PGC-1 α和SIRT 3作为治疗HD的治疗靶点。我们将确定R6/2和KI-zQ 175小鼠与SIRT 3过表达小鼠杂交是否会产生神经保护作用。我们将在饮食中给予烟酰胺核苷（NR）作为激活SIRT 1和SIRT 3的手段，并确定这是否在HD的R6/2和BACHD转基因小鼠模型中产生神经保护作用。最后，我们将确定panPPAR激动剂非诺贝特或RXR激动剂贝沙罗汀单独或联合给药是否会增加PGC-1 α的表达，并在R6/2和BACHD转基因小鼠中发挥神经保护作用。这些研究将验证PGC-1 α和SIRT 3作为治疗靶点，并将确定NR、非诺贝特和贝沙罗汀是否适合进一步的临床前开发，并最终用于临床试验，以确定其作为HD神经保护疗法的疗效。

 DESCRIPTION (provided by applicant): Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disease leading to both cognitive as well as motor deficits, and severe disability. The disease is caused by an unstable CAG repeat expansion which leads to a polyglutamine stretch within the protein huntingtin. The toxic effects of mutant huntingtin result in transcriptional dysregulation as well as mitochondrial dysfunction and oxidative damage. There is a deficiency of PGC-1alpha, a transcriptional coactivator which controls mitochondrial biogenesis and expression of antioxidant enzymes. There is also a deficiency of SIRT3, which is a protein deacetylase whose expression within mitochondria is dependent on PGC-1alpha. We propose validating both PGC-1alpha and SIRT3 as therapeutic targets for the treatment of HD. We will determine whether crossing both R6/2 and KI-zQ175 mice with SIRT3 overexpressing mice will produce neuroprotective effects. We will administer nicotinamide riboside (NR) in the diet as a means of activating SIRT1 and SIRT3, and determine whether this produces neuroprotective effects in both the R6/2 and the BACHD transgenic mouse models of HD. Lastly we will determine whether administration of the panPPAR agonist fenofibrate, or the RXR agonist bexarotene either alone or in combination will increase PGC-1alpha expression and exert neuroprotective effects in R6/2 and BACHD transgenic mice. These studies will validate PGC-1alpha and SIRT3 as therapeutic targets, and will determine whether NR, fenofibrate and bexarotene are suitable for further preclinical development, and ultimately for clinical trials to establish efficacy as neuroprotective therapies for HD.