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

Hazel Quek, John Luff, Ka Geen Cheung, Sergei Kozlov, Magtouf Gatei, C. Soon Lee, Mark C. Bellingham, Peter G. Noakes, Yi Chieh Lim, Nigel L. Barnett, Steven Dingwall, Ernst Wolvetang, Tomoji Mashimo, Tara L. Roberts, Martin F. Lavin

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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 para-hippocampus. 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.

Original languageEnglish
Pages (from-to)927-947
Number of pages21
JournalJournal of Leukocyte Biology
Volume101
Issue number4
DOIs
Publication statusPublished - 1 Apr 2017
Externally publishedYes

Fingerprint

Missense Mutation
DNA Damage
DNA
Spinal Cord
Paralysis
Hippocampus
Extremities
Phenotype
Ataxia Telangiectasia
Mutation
Inborn Genetic Diseases
Intracytoplasmic Sperm Injections
Medical Genetics
Microglia
Motor Neurons
Ataxia
Interleukin-1
Proline
Leucine
Cerebellum

Cite this

Quek, Hazel ; Luff, John ; Cheung, Ka Geen ; 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. / Rats with a missense mutation in Atm display neuroinflammation and neurodegeneration subsequent to accumulation of cytosolic DNA following unrepaired DNA damage. In: Journal of Leukocyte Biology. 2017 ; Vol. 101, No. 4. pp. 927-947.
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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 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 para-hippocampus. 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.",
author = "Hazel Quek and John Luff and Cheung, {Ka Geen} and Sergei Kozlov and Magtouf Gatei and Lee, {C. Soon} and Bellingham, {Mark C.} and Noakes, {Peter G.} and Lim, {Yi Chieh} and Barnett, {Nigel L.} and Steven Dingwall and Ernst Wolvetang and Tomoji Mashimo and Roberts, {Tara L.} and Lavin, {Martin F.}",
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Quek, H, Luff, J, Cheung, KG, Kozlov, S, Gatei, M, Lee, CS, Bellingham, MC, Noakes, PG, Lim, YC, Barnett, NL, Dingwall, S, Wolvetang, E, Mashimo, T, Roberts, TL & Lavin, MF 2017, '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, vol. 101, no. 4, pp. 927-947. https://doi.org/10.1189/jlb.4VMA0716-316R

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, Ka Geen; 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.

In: Journal of Leukocyte Biology, Vol. 101, No. 4, 01.04.2017, p. 927-947.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Rats with a missense mutation in Atm display neuroinflammation and neurodegeneration subsequent to accumulation of cytosolic DNA following unrepaired DNA damage

AU - Quek, Hazel

AU - Luff, John

AU - Cheung, Ka Geen

AU - Kozlov, Sergei

AU - Gatei, Magtouf

AU - Lee, C. Soon

AU - Bellingham, Mark C.

AU - Noakes, Peter G.

AU - Lim, Yi Chieh

AU - Barnett, Nigel L.

AU - Dingwall, Steven

AU - Wolvetang, Ernst

AU - Mashimo, Tomoji

AU - Roberts, Tara L.

AU - Lavin, Martin F.

PY - 2017/4/1

Y1 - 2017/4/1

N2 - 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 para-hippocampus. 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.

AB - 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 para-hippocampus. 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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U2 - 10.1189/jlb.4VMA0716-316R

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