title: Impaired hypoxic sensor Siah-1, PHD3, and FIH system in spinal motor neurons of an amyotrophic lateral sclerosis mouse model.
abstract: We recently reported spinal blood flow-metabolism uncoupling in the Cu/Zn-superoxide dismutase 1 (SOD1)-transgenic (Tg) mouse model of amyotrophic lateral sclerosis (ALS), suggesting relative hypoxia in the spinal cord. However, the hypoxic stress sensor pathway in ALS has not been well studied. In the present work, we examined the temporal and spatial changes of hypoxic stress sensor proteins (Siah-1, PHD3, and FIH) following motor neuron (MN) degeneration in the spinal cord of normoxic ALS mice. The expression of Siah-1 and PHD3 proteins progressively increased in the surrounding glial cells of presymptomatic Tg mice (10 weeks, 10 weeks) compared with the large MN of the anterior horn. In contrast, a significant reduction in Siah-1 and PHD3 protein expression was evident in end-stage ALS mice (18 weeks, 18 weeks). Double-immunofluorescence analysis revealed PHD3 plus Siah-1 double-positive cells in the surrounding glia of symptomatic Tg mice (14-18 weeks), with no change in the large MNs. In contrast, FIH protein expression decreased in the surrounding glial cells of Tg mice at end-stage ALS (18 weeks). The present study suggests a partial loss in the neuroprotective response of spinal MNs in ALS results from a relative hypoxia through the Siah-1, PHD3, and FIH system under normoxic conditions. This response could be an important mechanism of neurodegeneration in ALS.
authors.affiliation: Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Sato
authors.forename: Nobutoshi
authors.initials: N
authors.lastname: Morimoto
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kurata
authors.forename: Takafumi
authors.initials: T
authors.lastname: Mimoto
authors.forename: Kazunori
authors.initials: K
authors.lastname: Miyazaki
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Koji
authors.initials: K
authors.lastname: Abe
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology*; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009046:Motor Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism*; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D013116:Spinal Cord / Q000473:pathology*; D013482:Superoxide Dismutase / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000098563:Seven in Absentia Proteins
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; C410595:poly-U binding splicing factor 60KDa; D006899:Mixed Function Oxygenases; C522722:PHD3 protein, mouse; D011393:Procollagen-Proline Dioxygenase; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins