title: Early decrease of survival factors and DNA repair enzyme in spinal motor neurons of presymptomatic transgenic mice that express a mutant SOD1 gene.
abstract: The primary pathogenetic mechanisms of amyotrophic lateral sclerosis (ALS) have been elusive. Some of the mechanisms would be implicated in an imbalance between death and survival factors, and impairment of DNA repair possibly caused by oxidative stress. Phosphatidylinositol 3-kinase (PI3-K) and its downstream effector, Akt/protein kinase B (PKB), have been shown to play a pivotal role in neuronal survival against apoptosis supported by neurotrophic factors. To elucidate the mechanisms of motor neuron death in ALS, we examined the expression of PI3-K, Akt, and the DNA repair enzyme redox factor-1 (Ref-1) protein in the spinal cord of transgenic mice with an ALS-linked mutant Cu/Zn superoxide dismutase (SOD1) gene, a valuable model for human ALS. Immunoblotting and immunocytochemical analyses showed that most spinal motor neurons lost immunoreactivity for PI3-K, Akt, and Ref-1 in the presymptomatic stage that preceded a significant loss of neurons. These results suggest that an early decrease of survival signal proteins and a DNA repair enzyme in the spinal motor neurons may account for the mutant SOD1-mediated motor neuron death in this animal model of ALS.
authors.affiliation: Department of Neurology, Graduate School of Medicine and Dentistry, Okayama University, 2-5-1 Shikata-cho, 700-8558, Okayama, Japan. inagano@cc.okayama-u.ac.jp
authors.forename: Isao
authors.initials: I
authors.lastname: Nagano
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Murakami
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Manabe
authors.forename: Koji
authors.initials: K
authors.lastname: Abe
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000235:genetics; D000818:Animals; D000870:Anterior Horn Cells / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D002470:Cell Survival / Q000235:genetics; D004260:DNA Repair / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008822:Mice, Transgenic; D008970:Molecular Weight; D009046:Motor Neurons / Q000201:enzymology / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D013116:Spinal Cord / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D013482:Superoxide Dismutase / Q000235:genetics*
chemical_list: D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D013482:Superoxide Dismutase; C494918:AKT1 protein, human