Pharmacologic activation of mitochondrial biogenesis exerts widespread beneficial effects in a transgenic mouse model of Huntingtons disease
Pharmacologic activation of mitochondrial biogenesis exerts widespread beneficial effects in a transgenic mouse model of Huntingtons disease
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DOI：
10.1093/hmg/ddr541
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发表时间：
2012-03-01
影响因子：
3.5
通讯作者：
Beal, M. Flint
中科院分区：
文献类型：
--
作者：
Johri, Ashu;Calingasan, Noel Y.;Beal, M. Flint
大量证据表明，过氧化物酶体增殖物激活受体（PPAR）-辅激活因子1（PGC-1）水平和活性的损害在亨廷顿病（HD）的发病机制中起重要作用。我们测试了泛-PPAR激动剂苯扎贝特的药物治疗是否会纠正PGC-1的缺乏并在HD转基因小鼠模型中发挥有益作用。我们发现，在饮食中给予苯扎贝特使PGC-1、PPARs和下游基因的水平恢复到野生型小鼠的水平。表型和存活率有显著改善。在纹状体，星形胶质细胞增生和神经元萎缩减弱，线粒体数量增加。苯扎贝特治疗阻止了I型氧化肌纤维向II型糖酵解肌纤维的转化，并增加了肌肉线粒体的数量。最后，苯扎贝特挽救了HD小鼠的脂质蓄积和棕色脂肪组织的明显空泡化。这些发现提供了强有力的证据，证明苯扎贝特治疗可发挥神经保护作用，这可能有利于HD的治疗。
There is substantial evidence that impairment of peroxisome proliferator-activated receptor (PPAR)--coactivator 1 (PGC-1) levels and activity play an important role in Huntingtons disease (HD) pathogenesis. We tested whether pharmacologic treatment with the pan-PPAR agonist bezafibrate would correct a deficiency of PGC-1 and exert beneficial effects in a transgenic mouse model of HD. We found that administration of bezafibrate in the diet restored levels of PGC-1, PPARs and downstream genes to levels which occur in wild-type mice. There were significant improvements in phenotype and survival. In the striatum, astrogliosis and neuronal atrophy were attenuated and numbers of mitochondria were increased. Bezafibrate treatment prevented conversion of type I oxidative to type II glycolytic muscle fibers and increased the numbers of muscle mitochondria. Finally, bezafibrate rescued lipid accumulation and apparent vacuolization of brown adipose tissue in the HD mice. These findings provide strong evidence that treatment with bezafibrate exerts neuroprotective effects which may be beneficial in the treatment of HD.