Striatal mitochondrial proteins were investigated using proteomics in the 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Four proteins 19S proteasome ATPase, Rpt6 (19S Rpt6), Lectin-related nature killer cell receptor LY 49S, Zinc finger A20 domain containing 1, and the sodium channel-associated protein I isoform 2, were significantly decreased while alpha-synuclein was increased in MPTP-treated mice. The altered levels of 19S Rpt6 and alpha-synuclein were further verified by Western blot. Experiments using small interfering RNA (siRNA) showed that alpha-synuclein was increased by 50% in cultured striatal neurons when 19S Rpt6 was knocked down. Taken together, our results imply that a deficiency in 19S Rpt6 may be partially related to the MPTP-induced increase in alpha-synuclein in the striatum. (C) 2008 Published by Elsevier Inc.