Development of an α-synuclein knockdown peptide and evaluation of its efficacy in Parkinson’s disease models
Jack Wuyang Jin, Xuelai Fan, Esther del Cid‐Pellitero, Xingxing Liu, Limin Zhou, Chunfang Dai, Ebrima Gibbs, Wenting He, Hongjie Li, Xiaobin Wu, Austin Hill, Blair R. Leavitt, Neil R. Cashman, Lidong Liu, Jie Lu, Thomas M. Durcan, Zhifang Dong, Edward A. Fon, Yu Tian Wang
Abstract
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.