FLZ Attenuates α-Synuclein-Induced Neurotoxicity by Activating Heat Shock Protein 70
FLZ Attenuates α-Synuclein-Induced Neurotoxicity by Activating Heat Shock Protein 70
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DOI：
10.1007/s12035-015-9572-9
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发表时间：
2017-01-01
影响因子：
5.1
通讯作者：
Zhang, Dan
中科院分区：
文献类型：
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作者：
Bao, Xiu-Qi;Wang, Xiao-Liang;Zhang, Dan
帕金森病(Parkinson‘s Disease，PD)是第二常见的神经退行性疾病。帕金森病的病理是由多巴胺能神经元的进行性变性引起的，其特征是细胞内存在以α-突触核蛋白为主的路易小体。热休克蛋白(HSPs)在细胞蛋白质质量控制中起着至关重要的作用。HSP70尤其能阻止蛋白质聚集，如α-突触核蛋白，从而对帕金森病提供一定程度的保护。在以前的研究中，化合物Flz已被证明对几种PD模型具有保护作用，并被报道为HSP诱导剂，以保护MPP+诱导的神经毒性，但其机制尚不清楚。在这项研究中，我们研究了FLZ介导的HSP70在α-突触核蛋白转基因小鼠和细胞中的诱导作用。FLZ治疗减轻了α-突触核蛋白转基因小鼠的运动功能障碍，改善了多巴胺能神经元功能。经Flz处理后，HSP70蛋白表达和转录活性增加，导致α-突触核蛋白聚集减少和相关毒性降低。Qetetin或HSP70 siRNA对HSP70的抑制作用明显减弱了Flz的神经保护作用，证实了Flz通过HSP70发挥神经保护作用。我们发现，Flz直接结合并增加HSP70的辅伴侣Hip的表达，进而增强HSP70的活性。综上所述，我们确定了HSP70及其辅伴蛋白在预防神经退行性变中的关键作用，并提出靶向HSP70系统可能代表着一种潜在的治疗阿尔法突触核蛋白相关疾病的方法，如帕金森病。
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease. The pathology of PD is caused by progressive degeneration of dopaminergic neurons and is characterized by the presence of intracellular inclusions known as Lewy bodies, composed mainly of alpha-synuclein. Heat shock proteins (HSPs) are crucial in protein quality control in cells. HSP70 in particular prevents the aggregation of protein aggregation, such as alpha-synuclein, providing a degree of protection against PD. The compound FLZ has been shown to protect several PD models in previous studies and was reported as an HSP inducer to protect against MPP+-induced neurotoxicity, but the mechanism remains unclear. In this study, we investigated the effects of FLZ-mediated HSP70 induction in alpha-synuclein transgenic mice and cells. FLZ treatment alleviated motor dysfunction and improved dopaminergic neuronal function in alpha-synuclein transgenic mice. HSP70 protein expression and transcriptional activity were increased by FLZ treatment, eliciting a reduction of alpha-synuclein aggregation and associated toxicity. The inhibition of HSP70 by quercetin or HSP70 siRNA markedly attenuated the neuroprotective effects of FLZ, confirming that FLZ exerted a neuroprotective effect through HSP70. We revealed that FLZ directly bound to and increased the expression of Hip, a cochaperone of HSP70, which in turn enhanced HSP70 activity. In conclusion, we defined a critical role for HSP70 and its cochaperones activated by FLZ in preventing neurodegeneration and proposed that targeting the HSP70 system may represent a potential therapy for alpha-synuclein-related diseases, such as PD.