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.
Highlights
Convincing evidence supports the premise that reducing α-synuclein levels may be an effective therapy for Parkinson’s disease (PD); there has been lack of a clinically applicable α-synuclein reducing therapeutic strategy
We provide important evidence supporting that the Tat-βsyn-degron peptide, by rapidly and reversibly reducing the level of α-synuclein, may have therapeutic potential as a clinically applicable treatment for PD
We showed that the peptide-induced α-synuclein knockdown is associated with protection of dopaminergic neurons against toxin-induced damage in a culture model of PD
Summary
Convincing evidence supports the premise that reducing α-synuclein levels may be an effective therapy for Parkinson’s disease (PD); there has been lack of a clinically applicable α-synuclein reducing therapeutic strategy. 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. We report the development of a short, BBB and plasma membrane-permeant synthetic peptide that can rapidly reduce endogenous α-synuclein via proteasomal degradation Using both in vitro and in vivo models of PD, we provide proof-of-principle evidence for using this small α-synuclein knockdown peptide as a potential PD therapy
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