Jin et al develop and characterise a blood-brain barrier and plasma membrane-permeable α-synuclein knockdown peptide, Tat-βsyn-degron. In two mouse models of Parkinson’s disease, they show that Tat-βsyn-degron decreases α-synuclein aggregates and microglial activation as well as reducing neuronal damage and motor impairment. This study demonstrates the therapeutic potential of Tat-βsyn-degron in Parkinson’s disease treatment.