title: Rats with a missense mutation in Atm display neuroinflammation and neurodegeneration subsequent to accumulation of cytosolic DNA following unrepaired DNA damage.
abstract: Mutations in the ataxia-telangiectasia (A-T)-mutated (ATM) gene give rise to the human genetic disorder A-T, characterized by immunodeficiency, cancer predisposition, and neurodegeneration. Whereas a series of animal models recapitulate much of the A-T phenotype, they fail to present with ataxia or neurodegeneration. We describe here the generation of anAtmmissense mutant [amino acid change of leucine (L) to proline (P) at position 2262 (L2262P)] rat by intracytoplasmic injection (ICSI) of mutant sperm into oocytes.Atm-mutant rats (AtmL2262P/L2262P) expressed low levels of ATM protein, suggesting a destabilizing effect of the mutation, and had a significantly reduced lifespan compared withAtm+/+Whereas these rats did not show cerebellar atrophy, they succumbed to hind-limb paralysis (45%), and the remainder developed tumors. Closer examination revealed the presence of both dsDNA and ssDNA in the cytoplasm of cells in the hippocampus, cerebellum, and spinal cord ofAtmL2262P/L2262Prats. Significantly increased levels of IFN-β and IL-1β in all 3 tissues were indicative of DNA damage induction of the type 1 IFN response. This was further supported by NF-κB activation, as evidenced by p65 phosphorylation (P65) and translocation to the nucleus in the spinal cord and parahippocampus. Other evidence of neuroinflammation in the brain and spinal cord was the loss of motor neurons and the presence of increased activation of microglia. These data provide support for a proinflammatory phenotype that is manifested in theAtmmutant rat as hind-limb paralysis. This mutant represents a useful model to investigate the importance of neuroinflammation in A-T.
authors.affiliation: University of Queensland Centre for Clinical Research, Herston, Queensland, Australia.|Queensland Institute of Medical Research Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Hazel
authors.initials: H
authors.lastname: Quek
authors.affiliation: University of Queensland Centre for Clinical Research, Herston, Queensland, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Luff
authors.affiliation: University of Queensland Centre for Clinical Research, Herston, Queensland, Australia.|Queensland Institute of Medical Research Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: KaGeen
authors.initials: K
authors.lastname: Cheung
authors.affiliation: University of Queensland Centre for Clinical Research, Herston, Queensland, Australia.
authors.forename: Sergei
authors.initials: S
authors.lastname: Kozlov
authors.affiliation: University of Queensland Centre for Clinical Research, Herston, Queensland, Australia.
authors.forename: Magtouf
authors.initials: M
authors.lastname: Gatei
authors.affiliation: Ingham Institute for Applied Medical Research and School of Medicine, Western Sydney University, Liverpool, New South Wales, Australia.
authors.forename: C Soon
authors.initials: CS
authors.lastname: Lee
authors.affiliation: School of Biomedical Sciences, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Bellingham
authors.affiliation: School of Biomedical Sciences, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Noakes
authors.affiliation: Queensland Institute of Medical Research Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Yi Chieh
authors.initials: YC
authors.lastname: Lim
authors.affiliation: University of Queensland Centre for Clinical Research, Herston, Queensland, Australia.|Queensland Eye Institute, South Brisbane, Queensland, Australia.|School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Nigel L
authors.initials: NL
authors.lastname: Barnett
authors.affiliation: University of Queensland Centre for Clinical Research, Herston, Queensland, Australia.|Queensland Institute of Medical Research Berghofer Medical Research Institute, Herston, Queensland, Australia.|Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, Queensland, Australia; and.
authors.forename: Steven
authors.initials: S
authors.lastname: Dingwall
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, Queensland, Australia; and.
authors.forename: Ernst
authors.initials: E
authors.lastname: Wolvetang
authors.affiliation: Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Tomoji
authors.initials: T
authors.lastname: Mashimo
authors.affiliation: University of Queensland Centre for Clinical Research, Herston, Queensland, Australia; Tara.Roberts@westernsydney.edu.au.|Queensland Institute of Medical Research Berghofer Medical Research Institute, Herston, Queensland, Australia.|Ingham Institute for Applied Medical Research and School of Medicine, Western Sydney University, Liverpool, New South Wales, Australia.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Roberts
authors.affiliation: University of Queensland Centre for Clinical Research, Herston, Queensland, Australia; m.lavin@uq.edu.au.
authors.forename: Martin F
authors.initials: MF
authors.lastname: Lavin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001260:Ataxia Telangiectasia / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins / Q000737:chemistry / Q000235:genetics*; D001921:Brain / Q000473:pathology; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D007249:Inflammation / Q000235:genetics*; D016899:Interferon-beta / Q000378:metabolism; D008136:Longevity; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism; D009410:Nerve Degeneration / Q000235:genetics*; D010641:Phenotype; D021381:Protein Transport; D051381:Rats
chemical_list: D016328:NF-kappa B; D016899:Interferon-beta; D004247:DNA; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ataxia-telangiectasia; autoinflammatory; cGAS/STING; innate immunity