Recent studies have implicated alpha-synuclein (alpha-S) in the pathogenesis of Parkinson's disease (PD). The mechanisms underlying PD are not completely understood; however, mitochondrial complex I inhibition and oxidative injury may be involved. Because the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a potent complex I inhibitor that can cause oxidative injury and mimic many aspects of PD in treated animals, we sought to determine whether the overexpression of alpha-S in transgenic (tg) mice (alpha-S-tg) would enhance the substantia nigra (SN) pathology resulting from treatment with MPTP. For this purpose, alpha-S-tg mice were produced expressing high levels of wild-type (wt) human alpha-S under the control of the neuron-specific Thy-1 promoter. Alpha-S-tg mice and non-tg controls were treated with MPTP (15 mg/kg ip, twice a week for 2 weeks) or saline (Sal) and then examined 2 weeks after completion of treatment by transmission electron microscopy (EM). We found that alpha-S-tg mice treated with MPTP had extensive mitochondrial alterations, increases in mitochondrial size, filamentous neuritic aggregations, axonal degeneration, and formation of electron dense perinuclear cytoplasmic inclusions in the SN that did not occur in the hippocampus or neocortex, nor in MPTP-treated non-tg mice or Sal-treated alpha-S-tg mice. These findings support the potential involvement of alpha-S expression in the vulnerability of SN neurons to toxicity from mitochondrial complex I inhibitors and the subsequent development of neurodegenerative pathology.