Objective To observe nigral degeneration with inclusion body formation in rats and their behavioral changes after treatment with proteasome inhibitor, and investigate the role ofproteasomal dysfunction in the pathogenesis of Parkinson disease. Methods Lactacystin, a selective proteasome inhibitor, was injected stereotaxically into the lett substantia nigral pars compacta of the rats, and an equal volume of saline was injected in the control group. Spontaneous behavioral abnormalities and apomorphine-induced contralateral rotations of the rats were observed after the injection. The pathological changes in the substantia nigra were detected using Nissl staining, and the expressions of tyrosine hydroxylase (TH) and a-synuclein in the substantia nigra and TH expression in the striatum were investigated by immunohistochemistry. The ultrastructural changes in the substantia nigral pars compacta were observed with transmission electron microscope. Results Seven days after lactacystin injection, the rats exhibited reduced apontaneous activities, tremor, progressive bradykinesia, and apomorphine-induced contralateral rotation. Nissl staining 3 weeks after lactacystin injection revealed significantly reduced neurons in the lett substantia nigra pars compacta and loosened structures of the Nissl bodies;immunohistochemistry demonstrated obvious degeneration in the lett substantia nigra pars compacta, where the TH-positive cells were significantly decreased with enhanced expression of a-synuclein. The number of TH-positive fibers in the striamm was significantly reduced 3 weeks afterlactacystin injection, and electron microscopy revealed the formation of inclusion bodies as a result of protein aggregation. Conclusion Lactacystin injected stereotaxically into the lett substantia nigrai pars compacta can induce substantia nigra degeneration, inclusion body formation and behavioral changes in rats, suggesting the applicability of lactacystin for establishment of animal models of Parkinson disease. Proteasomal dysfunction may play an important role in the pathogenesis of Parkinson disease.