title: Motor neuron degeneration in amyotrophic lateral sclerosis mutant superoxide dismutase-1 transgenic mice: mechanisms of mitochondriopathy and cell death.
abstract: The mechanisms of human mutant superoxide dismutase-1 (mSOD1) toxicity to motor neurons (MNs) are unresolved. We show that MNs in G93A-mSOD1 transgenic mice undergo slow degeneration lacking similarity to apoptosis structurally and biochemically. It is characterized by somal and mitochondrial swelling and formation of DNA single-strand breaks prior to double-strand breaks occurring in nuclear and mitochondrial DNA. p53 and p73 are activated in degenerating MNs, but without nuclear import. The MN death is independent of activation of caspases-1, -3, and -8 or apoptosis-inducing factor within MNs, with a blockade of apoptosis possibly mediated by Aven up-regulation. MN swelling is associated with compromised Na,K-ATPase activity and aggregation. mSOD1 mouse MNs accumulate mitochondria from the axon terminals and generate higher levels of superoxide, nitric oxide, and peroxynitrite than MNs in control mice. Nitrated and aggregated cytochrome c oxidase subunit-I and alpha-synuclein as well as nitrated SOD2 accumulate in mSOD1 mouse spinal cord. Mitochondria in mSOD1 mouse MNs accumulate NADPH diaphorase and inducible nitric oxide synthase (iNOS)-like immunoreactivity, and iNOS gene deletion extends significantly the life span of G93A-mSOD1 mice. Prior to MN loss, spinal interneurons degenerate. These results identify novel mechanisms for mitochondriopathy and MN degeneration in amyotrophic lateral sclerosis (ALS) mice involving blockade of apoptosis, accumulation of MN mitochondria with enhanced toxic potential from distal terminals, NOS localization in MN mitochondria and peroxynitrite damage, and early degeneration of alpha-synuclein(+) interneurons. The data support roles for oxidative stress, protein nitration and aggregation, and excitotoxicity as participants in the process of MN degeneration caused by mSOD1.
authors.affiliation: Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196, USA. martinl@jhmi.edu
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Martin
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Liu
authors.forename: Kevin
authors.initials: K
authors.lastname: Chen
authors.forename: Ann C
authors.initials: AC
authors.lastname: Price
authors.forename: Yan
authors.initials: Y
authors.lastname: Pan
authors.forename: Jason A
authors.initials: JA
authors.lastname: Swaby
authors.forename: W Christopher
authors.initials: WC
authors.lastname: Golden
mesh_terms: D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000502:physiology; D053904:DNA Breaks, Single-Stranded; D004195:Disease Models, Animal; D006651:Histocytochemistry / Q000379:methods; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron / Q000379:methods; D008928:Mitochondria / Q000473:pathology*; D009410:Nerve Degeneration / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000502:physiology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D013482:Superoxide Dismutase / Q000235:genetics*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; D017382:Reactive Oxygen Species; D051636:X-Linked Inhibitor of Apoptosis Protein; D052248:Nitric Oxide Synthase Type I; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D000254:Sodium-Potassium-Exchanging ATPase