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Development of an α-synuclein knockdown peptide and evaluation of its efficacy in Parkinson's disease models.

Communications biology (2021-02-21)
Jack Wuyang Jin, Xuelai Fan, Esther Del Cid-Pellitero, Xing-Xing Liu, Limin Zhou, Chunfang Dai, Ebrima Gibbs, Wenting He, Hongjie Li, Xiaobin Wu, Austin Hill, Blair R Leavitt, Neil 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.

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