title: Mouse motor neuron disease caused by truncated SOD1 with or without C-terminal modification.
abstract: Mutation of Cu/Zn superoxide dismutase (SOD1) contributes to a portion of the cases of familial amyotrophic lateral sclerosis (FALS). We previously reported on a FALS family whose members had a mutant form of SOD1 characterized by a 2-base pair (bp) deletion at codon 126 of the SOD1 gene. To investigate the cellular consequences of this mutation, we produced transgenic mice that expressed normal and mutated copies of human SOD1: wild-type SOD1 (W), wild-type SOD1 with a FLAG epitope at C-terminal (WF), mutated SOD1 with the 2-bp deletion (D), and SOD1 with the 2-bp deletion with FLAG (DF). The mice heterozygotic for the human mutated SOD1 (D and DF) showed distinct ALS-like motor symptoms, whereas the mice heterozygotic for the normal SOD1 (W and WF) mice did not. Homozygotes of D and DF lines showed the ALS symptoms at an earlier age and died earlier than the heterozygotes. By Northern blot analysis, the mRNAs for all human SOD1s were confirmed in these lines. All the human SOD1 proteins, except the D mutant, were detectable by immunoblot. The D protein was only confirmed when it was concentrated by immunoprecipitation. Neuropathologically, loss of spinal motor neurons and reactive gliosis were common features in the symptomatic lines. The remaining motor neurons in these mice also exhibited eosinophilic inclusions. The biochemical and pathological characteristics of these mice are quite similar to those of human FALS patients with same mutation. This intriguing model will provide an important source of information of the pathogenesis of FALS.
authors.affiliation: Department of Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Nishi-cho 36-1,Yonago 683-8504, Japan. yawatana@grape.med.tottori-u.ac.jp
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yasui
authors.forename: Toshiya
authors.initials: T
authors.lastname: Nakano
authors.forename: Koji
authors.initials: K
authors.lastname: Doi
authors.forename: Yasuyo
authors.initials: Y
authors.lastname: Fukada
authors.forename: Michio
authors.initials: M
authors.lastname: Kitayama
authors.forename: Miho
authors.initials: M
authors.lastname: Ishimoto
authors.forename: Saiko
authors.initials: S
authors.lastname: Kurihara
authors.forename: Mika
authors.initials: M
authors.lastname: Kawashima
authors.forename: Hiroki
authors.initials: H
authors.lastname: Fukuda
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Adachi
authors.forename: Takao
authors.initials: T
authors.lastname: Inoue
authors.forename: Kenji
authors.initials: K
authors.lastname: Nakashima
mesh_terms: D000818:Animals; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D004195:Disease Models, Animal; D015870:Gene Expression / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D047468:Immunoprecipitation / Q000379:methods; D002479:Inclusion Bodies / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000502:physiology*; D016472:Motor Neuron Disease / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D009046:Motor Neurons / Q000201:enzymology / Q000473:pathology; D009154:Mutation; D009842:Oligopeptides; D010455:Peptides / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013116:Spinal Cord / Q000201:enzymology / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D013997:Time Factors
chemical_list: D005904:Glial Fibrillary Acidic Protein; D009842:Oligopeptides; D010455:Peptides; D012333:RNA, Messenger; C000606290:SOD1 protein, human; C085706:FLAG peptide; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1