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

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. and Lavin, Martin F. (2016) 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, 101 4: 927-947. doi:10.1189/jlb.4VMA0716-316R


Author 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.
Title Rats with a missense mutation in Atm display neuroinflammation and neurodegeneration subsequent to accumulation of cytosolic DNA following unrepaired DNA damage
Journal name Journal of Leukocyte Biology   Check publisher's open access policy
ISSN 0741-5400
1938-3673
Publication date 2016-11-28
Sub-type Article (original research)
DOI 10.1189/jlb.4VMA0716-316R
Open Access Status Not yet assessed
Volume 101
Issue 4
Start page 927
End page 947
Total pages 31
Place of publication Bethesda, MD, United States
Publisher Federation of American Societies for Experimental Biology
Collection year 2017
Language eng
Formatted 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 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 (AtmL2262P/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 AtmL2262P/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 .
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

 
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Created: Mon, 06 Feb 2017, 13:46:41 EST by Dr Mark Bellingham on behalf of School of Biomedical Sciences