A rat model of ataxia-telangiectasia: evidence for a neurodegenerative phenotype

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

Research output: Contribution to journalArticleResearchpeer-review

14 Citations (Scopus)

Abstract

Ataxia-telangiectasia (A-T), an autosomal recessive disease caused by mutations in the ATM gene is characterised by cerebellar atrophy and progressive neurodegeneration which has been poorly recapitulated in Atm mutant mice. Consequently, pathways leading to neurodegeneration in A-T are poorly understood. We describe here the generation of an Atm knockout rat model that does not display cerebellar atrophy but instead paralysis and spinal cord atrophy, reminiscent of that seen in older patients and milder forms of the disorder. Loss of Atm in neurons and glia leads to accumulation of cytosolic DNA, increased cytokine production and constitutive activation of microglia consistent with a neuroinflammatory phenotype. Rats lacking ATM had significant loss of motor neurons and microgliosis in the spinal cord, consistent with onset of paralysis. Since short term treatment with steroids has been shown to improve the neurological signs in A-T patients we determined if that was also the case for Atm-deficient rats. Betamethasone treatment extended the lifespan of Atm knockout rats, prevented microglial activation and significantly decreased neuroinflammatory changes and motor neuron loss. These results point to unrepaired damage to DNA leading to significant levels of cytosolic DNA in Atm-deficient neurons and microglia and as a consequence activation of the cGAS-STING pathway and cytokine production. This in turn would increase the inflammatory microenvironment leading to dysfunction and death of neurons. Thus the rat model represents a suitable one for studying neurodegeneration in A-T and adds support for the use of anti-inflammatory drugs for the treatment of neurodegeneration in A-T patients.

Original languageEnglish
Pages (from-to)109-123
Number of pages15
JournalHuman Molecular Genetics
Volume26
Issue number1
DOIs
Publication statusPublished - 1 Jan 2017
Externally publishedYes

Fingerprint

Ataxia Telangiectasia
Phenotype
Atrophy
Microglia
Motor Neurons
Neurons
Paralysis
Spinal Cord
Cytokines
Betamethasone
DNA
Neuroglia
DNA Damage
Anti-Inflammatory Agents
Therapeutics
Steroids
Mutation
Pharmaceutical Preparations
Genes

Cite this

Quek, H., Luff, J., Cheung, K. G., Kozlov, S., Gatei, M., Lee, C. S., ... Lavin, M. F. (2017). A rat model of ataxia-telangiectasia: evidence for a neurodegenerative phenotype. Human Molecular Genetics, 26(1), 109-123. https://doi.org/10.1093/hmg/ddw371
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. / A rat model of ataxia-telangiectasia : evidence for a neurodegenerative phenotype. In: Human Molecular Genetics. 2017 ; Vol. 26, No. 1. pp. 109-123.
@article{4e93225a174a4677b21b65f602f489b8,
title = "A rat model of ataxia-telangiectasia: evidence for a neurodegenerative phenotype",
abstract = "Ataxia-telangiectasia (A-T), an autosomal recessive disease caused by mutations in the ATM gene is characterised by cerebellar atrophy and progressive neurodegeneration which has been poorly recapitulated in Atm mutant mice. Consequently, pathways leading to neurodegeneration in A-T are poorly understood. We describe here the generation of an Atm knockout rat model that does not display cerebellar atrophy but instead paralysis and spinal cord atrophy, reminiscent of that seen in older patients and milder forms of the disorder. Loss of Atm in neurons and glia leads to accumulation of cytosolic DNA, increased cytokine production and constitutive activation of microglia consistent with a neuroinflammatory phenotype. Rats lacking ATM had significant loss of motor neurons and microgliosis in the spinal cord, consistent with onset of paralysis. Since short term treatment with steroids has been shown to improve the neurological signs in A-T patients we determined if that was also the case for Atm-deficient rats. Betamethasone treatment extended the lifespan of Atm knockout rats, prevented microglial activation and significantly decreased neuroinflammatory changes and motor neuron loss. These results point to unrepaired damage to DNA leading to significant levels of cytosolic DNA in Atm-deficient neurons and microglia and as a consequence activation of the cGAS-STING pathway and cytokine production. This in turn would increase the inflammatory microenvironment leading to dysfunction and death of neurons. Thus the rat model represents a suitable one for studying neurodegeneration in A-T and adds support for the use of anti-inflammatory drugs for the treatment of neurodegeneration in A-T patients.",
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.}",
year = "2017",
month = "1",
day = "1",
doi = "10.1093/hmg/ddw371",
language = "English",
volume = "26",
pages = "109--123",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "1",

}

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, 'A rat model of ataxia-telangiectasia: evidence for a neurodegenerative phenotype' Human Molecular Genetics, vol. 26, no. 1, pp. 109-123. https://doi.org/10.1093/hmg/ddw371

A rat model of ataxia-telangiectasia : evidence for a neurodegenerative phenotype. / 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: Human Molecular Genetics, Vol. 26, No. 1, 01.01.2017, p. 109-123.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A rat model of ataxia-telangiectasia

T2 - evidence for a neurodegenerative phenotype

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 - 2017/1/1

Y1 - 2017/1/1

N2 - Ataxia-telangiectasia (A-T), an autosomal recessive disease caused by mutations in the ATM gene is characterised by cerebellar atrophy and progressive neurodegeneration which has been poorly recapitulated in Atm mutant mice. Consequently, pathways leading to neurodegeneration in A-T are poorly understood. We describe here the generation of an Atm knockout rat model that does not display cerebellar atrophy but instead paralysis and spinal cord atrophy, reminiscent of that seen in older patients and milder forms of the disorder. Loss of Atm in neurons and glia leads to accumulation of cytosolic DNA, increased cytokine production and constitutive activation of microglia consistent with a neuroinflammatory phenotype. Rats lacking ATM had significant loss of motor neurons and microgliosis in the spinal cord, consistent with onset of paralysis. Since short term treatment with steroids has been shown to improve the neurological signs in A-T patients we determined if that was also the case for Atm-deficient rats. Betamethasone treatment extended the lifespan of Atm knockout rats, prevented microglial activation and significantly decreased neuroinflammatory changes and motor neuron loss. These results point to unrepaired damage to DNA leading to significant levels of cytosolic DNA in Atm-deficient neurons and microglia and as a consequence activation of the cGAS-STING pathway and cytokine production. This in turn would increase the inflammatory microenvironment leading to dysfunction and death of neurons. Thus the rat model represents a suitable one for studying neurodegeneration in A-T and adds support for the use of anti-inflammatory drugs for the treatment of neurodegeneration in A-T patients.

AB - Ataxia-telangiectasia (A-T), an autosomal recessive disease caused by mutations in the ATM gene is characterised by cerebellar atrophy and progressive neurodegeneration which has been poorly recapitulated in Atm mutant mice. Consequently, pathways leading to neurodegeneration in A-T are poorly understood. We describe here the generation of an Atm knockout rat model that does not display cerebellar atrophy but instead paralysis and spinal cord atrophy, reminiscent of that seen in older patients and milder forms of the disorder. Loss of Atm in neurons and glia leads to accumulation of cytosolic DNA, increased cytokine production and constitutive activation of microglia consistent with a neuroinflammatory phenotype. Rats lacking ATM had significant loss of motor neurons and microgliosis in the spinal cord, consistent with onset of paralysis. Since short term treatment with steroids has been shown to improve the neurological signs in A-T patients we determined if that was also the case for Atm-deficient rats. Betamethasone treatment extended the lifespan of Atm knockout rats, prevented microglial activation and significantly decreased neuroinflammatory changes and motor neuron loss. These results point to unrepaired damage to DNA leading to significant levels of cytosolic DNA in Atm-deficient neurons and microglia and as a consequence activation of the cGAS-STING pathway and cytokine production. This in turn would increase the inflammatory microenvironment leading to dysfunction and death of neurons. Thus the rat model represents a suitable one for studying neurodegeneration in A-T and adds support for the use of anti-inflammatory drugs for the treatment of neurodegeneration in A-T patients.

UR - http://www.scopus.com/inward/record.url?scp=85030442082&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddw371

DO - 10.1093/hmg/ddw371

M3 - Article

VL - 26

SP - 109

EP - 123

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 1

ER -