Abstract Fibrillization and aggregation of α-synuclein may play a critical role in neurodegenerative diseases like Parkinson’s diseases. Adeno-associated virus (AAV) vector delivery of an α-synuclein ribozyme was tested for its silencing effect on degenerating nigrostriatal neurons in the MPP + model of Parkinson’s disease. We designed α-synuclein ribozyme against human α-synuclein gene expression and constructed α-synuclein ribozymes-carrying rAAV vector (designated rAAV-SynRz). Co-transfection of rAAV-SynRz and rAAV-α-synuclein into HEK293 cells resulted in down-regulation of α-synuclein protein expression in vitro. Then, rAAV-SynRz was injected into the substantia nigra (SN) of MPP +-treated rats. Cell counts of TH-positive neurons in the SN revealed that rAAV-SynRz significantly protected TH-positive cells against apoptotic death, compared with those of rAAV-EGFP or no rAAV injected rats. Our results indicate that the use of rAAV-SynRz allowed the survival of higher number of TH-positive neurons in SN in the MPP + model. Down-regulation of α-synuclein expression could be potentially a suitable target for gene therapy of Parkinson’s disease.