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This study was undertaken to develop a blood-brain barrier and plasma membrane-permeable \u03b1-synuclein knockdown peptide, Tat-\u03b2syn-degron, that may have therapeutic potential. The peptide effectively reduced the level of \u03b1-synuclein via proteasomal degradation both in cell cultures and in animals. Tat-\u03b2syn-degron decreased \u03b1-synuclein aggregates and microglial activation in an \u03b1-synuclein pre-formed fibril model of spreading synucleinopathy in transgenic mice overexpressing human A53T \u03b1-synuclein. Moreover, Tat-\u03b2syn-degron reduced \u03b1-synuclein levels and significantly decreased the parkinsonian toxin-induced neuronal damage and motor impairment in a mouse toxicity model of PD. 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