Enhanced substantia nigra mitochondrial pathology in human α-synuclein transgenic mice after treatment with MPTP

• Published in: Experimental neurology Vol. 186; no. 2; pp. 158 - 172
• Main Authors: Song, David D., Shults, Clifford W., Sisk, Abbyann, Rockenstein, Edward, Masliah, Eliezer
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2004
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - pharmacology; alpha-Synuclein; Animals; Dopamine Agents - pharmacology; Dose-Response Relationship, Drug; Electron microscopy; Humans; Inclusion bodies; Lewy bodies; Lewy Bodies - drug effects; Lewy Bodies - pathology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Electron - methods; Mitochondria; Mitochondria - pathology; Mitochondria - ultrastructure; Nerve Degeneration - chemically induced; Nerve Degeneration - pathology; Nerve Tissue Proteins - genetics; Oxidative stress; Parkinson's disease; Reverse Transcriptase Polymerase Chain Reaction - methods; Substantia Nigra - drug effects; Substantia Nigra - pathology; Substantia Nigra - ultrastructure; Synucleins; Thy-1 Antigens - metabolism; α-Synuclein; α-Synuclein; Oxidative stress; Mitochondria; Parkinson's disease; Inclusion bodies; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Electron microscopy; Lewy bodies
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/S0014-4886(03)00342-X

Recent studies have implicated α-synuclein (α-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 α-S in transgenic ( tg) mice (α-S- tg) would enhance the substantia nigra (SN) pathology resulting from treatment with MPTP. For this purpose, α-S- tg mice were produced expressing high levels of wild-type ( wt) human α-S under the control of the neuron-specific Thy-1 promoter. α-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 α-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 α-S- tg mice. These findings support the potential involvement of α-S expression in the vulnerability of SN neurons to toxicity from mitochondrial complex I inhibitors and the subsequent development of neurodegenerative pathology.