Parkinson’s disease (PD) is a major neurodegenerative disorder that affects 5 million people worldwide. To date, there is no effective treatment that directly targets the causes of the disease. Current clinical approaches, like deep brain stimulation and pharmacological treatments with levodopa and dopamine agonists, are only symptom-relieving and their efficacy is largely limited by their undesirable complications and side effects. Accumulating evidence supports that nigral neuronal loss in PD is at least in part associated with aggregation of α-synuclein in the cytoplasm. Knockdown of α-synuclein using genetic manipulations such as siRNAs has been shown to protect dopaminergic neurons from parkinsonian toxin-induced cell death both in vitro and in vivo. However, the translation of siRNA into clinical application has been hindered in part due to its inability to cross the blood brain barrier (BBB) and the neuronal membrane. To this end, using the peptide-mediated protein knockdown technology, we developed a membrane-permeant peptide PP-003 that can knock down endogenous α-synuclein protein with high efficacy and specificity and thereby protect against parkinsonian toxin MPTP-induced neuronal damages in mice.