Treatment with Trehalose Prevents Behavioral and Neurochemical Deficits Produced in an AAV α-Synuclein Rat Model of Parkinson's Disease
Treatment with Trehalose Prevents Behavioral and Neurochemical Deficits Produced in an AAV α-Synuclein Rat Model of Parkinson's Disease
复制标题
海藻糖治疗可预防帕金森病 AAV α-突触核蛋白大鼠模型中产生的行为和神经化学缺陷
DOI：
10.1007/s12035-015-9173-7
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发表时间：
2016-05-01
影响因子：
5.1
通讯作者：
Wang, Jian
中科院分区：
文献类型：
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作者：
He, Qing;Koprich, James B.;Wang, Jian
多巴胺 (DA) 神经元中错误折叠的 α-突触核蛋白的积累被认为在帕金森病 (PD) 的发病机制中具有重要意义。基于病毒载体介导的α-突触核蛋白过度表达的帕金森病动物模型已经开发出来，并显示出多巴胺能毒性的证据，为我们研究干扰α-突触核蛋白介导的病理学的潜在疗法提供了一个很好的工具。有效的缓解疾病的治疗分子应该能够干扰α-突触核蛋白聚集的神经毒性。我们的研究强调了自噬增强剂海藻糖（饮用水中浓度为 5% 和 2%）能够在基于腺相关病毒血清型 1/2 (AAV1/2) 的 PD 大鼠模型中防止 A53T α-突触核蛋白介导的 DA 变性。行为测试和神经化学分析表明，通过在 AAV 递送的同时开始 5% 和 2% 海藻糖，α-突触核蛋白介导的运动不对称和 DA 神经变性缺陷（包括 DA 神经元存活和 DA 周转受损，以及黑质纹状体系统中 α-突触核蛋白积累和聚集）显着减弱。海藻糖（0.5%）对上述行为和神经化学缺陷无效。进一步的研究表明，海藻糖通过增加 LC3-II 的形成来增强纹状体中的自噬。这项研究支持使用海藻糖作为一种新的治疗策略的概念，可以预防/逆转 α-突触核蛋白聚集来治疗帕金森病。
The accumulation of misfolded alpha-synuclein in dopamine (DA) neurons is believed to be of major importance in the pathogenesis of Parkinson's disease (PD). Animal models of PD, based on viral-vector-mediated over-expression of alpha-synuclein, have been developed and show evidence of dopaminergic toxicity, providing us a good tool to investigate potential therapies to interfere with alpha-synuclein-mediated pathology. An efficient disease-modifying therapeutic molecule should be able to interfere with the neurotoxicity of alpha-synuclein aggregation. Our study highlighted the ability of an autophagy enhancer, trehalose (at concentrations of 5 and 2 % in drinking water), to protect against A53T alpha-synuclein-mediated DA degeneration in an adeno-associated virus serotype 1/2 (AAV1/2)-based rat model of PD. Behavioral tests and neurochemical analysis demonstrated a significant attenuation in alpha-synuclein-mediated deficits in motor asymmetry and DA neurodegeneration including impaired DA neuronal survival and DA turnover, as well as alpha-synuclein accumulation and aggregation in the nigrostriatal system by commencing 5 and 2 % trehalose at the same time as delivery of AAV. Trehalose (0.5 %) was ineffective on the above behavioral and neurochemical deficits. Further investigation showed that trehalose enhanced autophagy in the striatum by increasing formation of LC3-II. This study supports the concept of using trehalose as a novel therapeutic strategy that might prevent/reverse alpha-synuclein aggregation for the treatment of PD.