Rats with a missense mutation in Atm display neuroinflammation and neurodegeneration subsequent to accumulation of cytosolic DNA following unrepaired DNA damage

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

Noakes, Peter G.¹  Wolvetang, Ernst¹  Barnett, Nigel L.¹  Lee, C. Soon¹  Cheung, KaGeen¹  Roberts, Tara L.¹  Gatei, Magtouf⁶  Dingwall, Steven^1,10  Lavin, Martin F.^1,12  Mashimo, Tomoji^1,12  Luff, John^1,13  Kozlov, Sergei^1,13  Lim, Yi Chieh^1,13  Bellingham, Mark C.^1,13 

[1] and;..Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, Queensland, Australia;..Ingham Institute for Applied Medical Research and School of Medicine, Western Sydney University, Liverpool, New South Wales, Australia;..Queensland Eye Institute, South Brisbane, Queensland, Australia;..Queensland Institute of Medical Research Berghofer Medical Research Institute, Herston, Queensland, Australia;..School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia;Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, Queensland, Australia;Graduate School of Medicine, Osaka University, Osaka, Japan;Ingham Institute for Applied Medical Research and School of Medicine, Western Sydney University, Liverpool, New South Wales, Australia;Queensland Institute of Medical Research Berghofer Medical Research Institute, Herston, Queensland, Australia;School of Biomedical Sciences, University of Queensland, St Lucia, Queensland, Australia;University of Queensland Centre for Clinical Research, Herston, Queensland, Australia

关键词: innate immunity;    autoinflammatory;    ataxia‐;    telangiectasia;    cGAS/STING;   

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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 an Atm missense 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 (Atm^{L2262P/L2262P}) expressed low levels of ATM protein, suggesting a destabilizing effect of the mutation, and had a significantly reduced lifespan compared with Atm^+/+. 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 of Atm^{L2262P/L2262P} rats. 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 the Atm mutant rat as hind-limb paralysis. This mutant represents a useful model to investigate the importance of neuroinflammation in A-T.

【 授权许可】

CC BY