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Development of an α-synuclein knockdown peptide and evaluation of its efficacy in Parkinson’s disease models
Communications Biology ( IF 5.2 ) Pub Date : 2021-02-19 , DOI: 10.1038/s42003-021-01746-6
Jack Wuyang Jin 1 , Xuelai Fan 1 , Esther Del Cid-Pellitero 2 , Xing-Xing Liu 2 , Limin Zhou 3, 4, 5, 6 , Chunfang Dai 3, 4, 5, 6 , Ebrima Gibbs 1 , Wenting He 3, 4, 5, 6 , Hongjie Li 3, 4, 5, 6 , Xiaobin Wu 3, 4, 5, 6 , Austin Hill 7 , Blair R Leavitt 7 , Neil Cashman 1 , Lidong Liu 1 , Jie Lu 1 , Thomas M Durcan 2 , Zhifang Dong 3, 4, 5, 6 , Edward A Fon 2 , Yu Tian Wang 1
Affiliation  

Convincing evidence supports the premise that reducing α-synuclein levels may be an effective therapy for Parkinson’s disease (PD); however, there has been lack of a clinically applicable α-synuclein reducing therapeutic strategy. This study was undertaken to develop a blood-brain barrier and plasma membrane-permeable α-synuclein knockdown peptide, Tat-βsyn-degron, that may have therapeutic potential. The peptide effectively reduced the level of α-synuclein via proteasomal degradation both in cell cultures and in animals. Tat-βsyn-degron decreased α-synuclein aggregates and microglial activation in an α-synuclein pre-formed fibril model of spreading synucleinopathy in transgenic mice overexpressing human A53T α-synuclein. Moreover, Tat-βsyn-degron reduced α-synuclein levels and significantly decreased the parkinsonian toxin-induced neuronal damage and motor impairment in a mouse toxicity model of PD. These results show the promising efficacy of Tat-βsyn-degron in two different animal models of PD and suggest its potential use as an effective PD therapeutic that directly targets the disease-causing process.



中文翻译:


α-突触核蛋白敲低肽的开发及其在帕金森病模型中的功效评估



令人信服的证据支持这样的前提:降低 α-突触核蛋白水平可能是帕金森病 (PD) 的有效疗法;然而,一直缺乏临床适用的α-突触核蛋白减少治疗策略。这项研究的目的是开发一种血脑屏障和质膜可渗透的 α-突触核蛋白敲低肽 Tat-βsyn-degron,它可能具有治疗潜力。该肽通过细胞培养物和动物中的蛋白酶体降解有效降低 α-突触核蛋白的水平。在过表达人 A53T α-突触核蛋白的转基因小鼠中,在传播突触核蛋白病的 α-突触核蛋白预形成原纤维模型中,Tat-βsyn-degron 降低了 α-突触核蛋白聚集体和小胶质细胞活化。此外,在帕金森病小鼠毒性模型中,Tat-βsyn-degron 降低了 α-突触核蛋白水平,并显着降低了帕金森毒素诱导的神经元损伤和运动障碍。这些结果表明 Tat-βsyn-degron 在两种不同的 PD 动物模型中具有良好的功效,并表明其有可能用作直接针对致病过程的有效 PD 治疗剂。

更新日期:2021-02-19
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