Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice
Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice
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DOI：
10.1073/pnas.0536856100
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发表时间：
2003-03-04
影响因子：
11.1
通讯作者：
Mattson, MP
中科院分区：
文献类型：
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作者：
Duan, WZ;Guo, ZH;Mattson, MP
除了神经功能缺陷外，亨廷顿氏病（HD）患者和表达突变人类亨廷顿蛋白的转基因小鼠表现出脑源性神经营养因子、高血糖和组织消耗水平降低。我们发现，亨廷顿蛋白突变小鼠（一种HD动物模型）的神经病理（亨廷顿蛋白包涵体的形成和凋亡蛋白酶的激活）、行为（运动功能障碍）和代谢（葡萄糖耐受不良和组织消耗）异常的进展，在维持饮食限制（DR）喂养方案的情况下得到延缓，从而延长了它们的寿命。DR增加了纹状体和皮层中脑源性神经营养因子和蛋白伴侣热休克蛋白-70的水平，这些在喂食正常饮食的HD小鼠中被耗尽。DR对HD小鼠致病过程的抑制表明，突变的亨廷顿蛋白通过损害细胞抗逆性来促进神经元变性，并且HD的身体消瘦是由神经变性过程驱动的。我们的研究结果表明，饮食干预可能会抑制疾病进程，并延长携带突变亨廷顿基因的人类的寿命。
In addition to neurological deficits, Huntington's disease (HD) patients and transgenic mice expressing mutant human huntingtin exhibit reduced levels of brain-derived neurotrophic factor, hyperglycemia, and tissue wasting. We show that the progression of neuropathological (formation of huntingtin inclusions and apoptotic protease activation), behavioral (motor dysfunction), and metabolic (glucose intolerance and tissue wasting) abnormalities in huntingtin mutant mice, an animal model of HD, are retarded when the mice are maintained on a dietary restriction (DR) feeding regimen resulting in an extension of their life span. DR increases levels of brain-derived neurotrophic factor and the protein chaperone heat-shock protein-70 in the striatum and cortex, which are depleted in HD mice fed a normal diet. The suppression of the pathogenic processes by DR in HD mice suggests that mutant huntingtin promotes neuronal degeneration by impairing cellular stress resistance, and that the body wasting in HD is driven by the neurodegenerative process. Our findings suggest a dietary intervention that may suppress the disease process and increase the life span of humans that carry the mutant huntingtin gene.