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

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) A rat model of ataxia-telangiectasia: evidence for a neurodegenerative phenotype. Human Molecular Genetics, 26 1: 109-123. doi:10.1093/hmg/ddw371

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 A rat model of ataxia-telangiectasia: evidence for a neurodegenerative phenotype
Journal name Human Molecular Genetics   Check publisher's open access policy
ISSN 0964-6906
Publication date 2016-11-26
Sub-type Article (original research)
DOI 10.1093/hmg/ddw371
Open Access Status Not Open Access
Volume 26
Issue 1
Start page 109
End page 123
Total pages 15
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Collection year 2017
Language eng
Formatted 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.
Keyword ATM gene
Autosomal recessive disease
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

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Created: Mon, 06 Feb 2017, 13:37:35 EST by Dr Mark Bellingham on behalf of School of Biomedical Sciences