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.

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。