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

Authors: Quek, Hazel  Luff, John  Cheung, KaGeen  Kozlov, Sergei  Gatei, Magtouf  Lee, C Soon  Bellingham, Mark C  Noakes, Peter G  Lim, Yi Chieh  Barnett, Nigel L  Dingwall, Steven  Wolvetang, Ernst  Mashimo, Tomoji  Roberts, Tara L  Lavin, Martin F 
Citation: Quek H, etal., J Leukoc Biol. 2017 Apr;101(4):927-947. doi: 10.1189/jlb.4VMA0716-316R. Epub 2016 Nov 28.
Pubmed: (View Article at PubMed) PMID:27895165
DOI: Full-text: DOI:10.1189/jlb.4VMA0716-316R

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-ß and IL-1ß 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.

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CRRD Object Information
CRRD ID: 12879393
Created: 2017-04-18
Species: All species
Last Modified: 2017-04-18
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.