Rapamycin improves motor function, reduces 4-hydroxynonenal adducted protein in brain, and attenuates synaptic injury in a mouse model of synucleinopathy.
Rapamycin improves motor function, reduces 4-hydroxynonenal adducted protein in brain, and attenuates synaptic injury in a mouse model of synucleinopathy.
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DOI：
10.3402/pba.v5.28743
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Strong R
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文献类型：
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作者：
Bai X;Wey MC;Fernandez E;Hart MJ;Gelfond J;Bokov AF;Rani S;Strong R
突触核蛋白病是一组与年龄相关的神经退行性疾病中的任何一种，包括帕金森病、多系统萎缩和路易体痴呆，其特征是α-突触核蛋白夹杂物和帕金森氏症运动缺陷，影响着全球数百万患者。但是目前还没有治愈突触核蛋白病的方法。雷帕霉素已在几种体外和体内突触核蛋白病模型中显示出神经保护作用。然而，还没有关于RAPA对突触核蛋白病模型中运动功能或神经变性测量的长期影响的报道。我们确定长期喂食雷帕霉素饮食（饮食中14 ppm; 2.25 mg/kg体重/天）是否改善神经元A53 T α-突触核蛋白转基因小鼠（TG）的运动功能，并使用各种行为和生化方法探索潜在机制。治疗24周后，雷帕霉素改善了前爪步进调节试验、加速旋转杆和杆试验的表现。雷帕霉素不改变A53T α-突触核蛋白含量。雷帕霉素处理对中脑或纹状体单胺或其代谢产物没有影响。加合到脂质过氧化产物4-羟基壬烯醛的蛋白质在用雷帕霉素处理的野生型和TG小鼠的脑区域中减少。在TG小鼠的几个脑区发现突触前标记物突触素水平降低。雷帕霉素减弱了受影响脑区突触素蛋白的丢失。雷帕霉素还减弱了突触素蛋白的丢失，并防止了4-羟基壬烯醛处理的SH-SY5Y细胞中神经突长度的减少。综上所述，这些数据表明，雷帕霉素，FDA批准的药物，可能证明在治疗突触核蛋白病有用。
Synucleinopathy is any of a group of age-related neurodegenerative disorders including Parkinson's disease, multiple system atrophy, and dementia with Lewy Bodies, which is characterized by α-synuclein inclusions and parkinsonian motor deficits affecting millions of patients worldwide. But there is no cure at present for synucleinopathy. Rapamycin has been shown to be neuroprotective in several in vitro and in vivo synucleinopathy models. However, there are no reports on the long-term effects of RAPA on motor function or measures of neurodegeneration in models of synucleinopathy. We determined whether long-term feeding a rapamycin diet (14 ppm in diet; 2.25 mg/kg body weight/day) improves motor function in neuronal A53T α-synuclein transgenic mice (TG) and explored underlying mechanisms using a variety of behavioral and biochemical approaches. After 24 weeks of treatment, rapamycin improved performance on the forepaw stepping adjustment test, accelerating rotarod and pole test. Rapamycin did not alter A53T α-synuclein content. There was no effect of rapamycin treatment on midbrain or striatal monoamines or their metabolites. Proteins adducted to the lipid peroxidation product 4-hydroxynonenal were decreased in brain regions of both wild-type and TG mice treated with rapamycin. Reduced levels of the presynaptic marker synaptophysin were found in several brain regions of TG mice. Rapamycin attenuated the loss of synaptophysin protein in the affected brain regions. Rapamycin also attenuated the loss of synaptophysin protein and prevented the decrease of neurite length in SH-SY5Y cells treated with 4-hydroxynonenal. Taken together, these data suggest that rapamycin, an FDA approved drug, may prove useful in the treatment of synucleinopathy.