RGD Reference Report - A rat model of ataxia-telangiectasia: evidence for a neurodegenerative phenotype. - Rat Genome Database

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

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., Hum Mol Genet. 2017 Jan 1;26(1):109-123. doi: 10.1093/hmg/ddw371.
RGD ID: 12879399
Pubmed: PMID:28007901   (View Abstract at PubMed)
DOI: DOI:10.1093/hmg/ddw371   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
ATMHumanataxia telangiectasia  ISOAtm (Rattus norvegicus)DNA:deletion:exon:RGD 
AtmMouseataxia telangiectasia  ISOAtm (Rattus norvegicus)DNA:deletion:exon:RGD 
AtmRatataxia telangiectasia  IMP DNA:deletion:exon:RGD 
Atmem1KyoRatataxia telangiectasia  IMP  RGD 
F344-Atmem1KyoRatataxia telangiectasia  IMP  RGD 
ATMHumandisease of cellular proliferation  ISOAtm (Rattus norvegicus) RGD 
AtmMousedisease of cellular proliferation  ISOAtm (Rattus norvegicus) RGD 
AtmRatdisease of cellular proliferation  IMP  RGD 
Atmem1KyoRatdisease of cellular proliferation  IMP  RGD 
F344-Atmem1KyoRatdisease of cellular proliferation  IMP  RGD 
ATMHumaninfertility  ISOAtm (Rattus norvegicus)DNA:deletion:exon:RGD 
AtmMouseinfertility  ISOAtm (Rattus norvegicus)DNA:deletion:exon:RGD 
AtmRatinfertility  IMP DNA:deletion:exon:RGD 
Atmem1KyoRatinfertility  IMP  RGD 
F344-Atmem1KyoRatinfertility  IMP  RGD 
ATMHumanleukemia  ISOAtm (Rattus norvegicus)DNA:deletion:exon:RGD 
AtmMouseleukemia  ISOAtm (Rattus norvegicus)DNA:deletion:exon:RGD 
AtmRatleukemia  IMP DNA:deletion:exon:RGD 
Atmem1KyoRatleukemia  IMP  RGD 
F344-Atmem1KyoRatleukemia  IMP  RGD 
ATMHumanlymphoma  ISOAtm (Rattus norvegicus)DNA:deletion:exon:RGD 
AtmMouselymphoma  ISOAtm (Rattus norvegicus)DNA:deletion:exon:RGD 
AtmRatlymphoma  IMP DNA:deletion:exon:RGD 
Atmem1KyoRatlymphoma  IMP  RGD 
F344-Atmem1KyoRatlymphoma  IMP  RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
AtmRatcellular response to ionizing radiation  IMP  RGD 
AtmRatregulation of microglial cell activation  IMP  RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
AtmRatabnormal microglial cell activation  IMP  RGD 
Atmem1KyoRatabnormal microglial cell activation  IMP  RGD 
F344-Atmem1KyoRatabnormal microglial cell activation  IMP  RGD 
AtmRatabnormal microglial cell morphology  IMP DNA:deletion:exon:RGD 
Atmem1KyoRatabnormal microglial cell morphology  IMP  RGD 
AtmRatabnormal ovarian folliculogenesis  IMP DNA:deletion:exon:RGD 
Atmem1KyoRatabnormal ovarian folliculogenesis  IMP  RGD 
F344-Atmem1KyoRatabnormal ovarian folliculogenesis  IMP  RGD 
AtmRatabnormal seminiferous tubule morphology  IMP DNA:deletion:exon:RGD 
Atmem1KyoRatabnormal seminiferous tubule morphology  IMP  RGD 
F344-Atmem1KyoRatabnormal seminiferous tubule morphology  IMP  RGD 
AtmRatdecreased microglial cell number  IMP  RGD 
Atmem1KyoRatdecreased microglial cell number  IMP  RGD 
F344-Atmem1KyoRatdecreased microglial cell number  IMP  RGD 
AtmRatdecreased motor neuron number  IMP DNA:deletion:exon:RGD 
Atmem1KyoRatdecreased motor neuron number  IMP  RGD 
F344-Atmem1KyoRatdecreased motor neuron number  IMP  RGD 
AtmRathindlimb paralysis  IMP DNA:deletion:exon:RGD 
Atmem1KyoRathindlimb paralysis  IMP  RGD 
Atmm1KyoRathindlimb paralysis  IMP  RGD 
F344-Atmem1KyoRathindlimb paralysis  IMP  RGD 
F344-Atmm1KyoRathindlimb paralysis  IMP  RGD 
AtmRatincreased microglial cell activation  IMP DNA:deletion:exon:RGD 
Atmem1KyoRatincreased microglial cell activation  IMP  RGD 
AtmRatmicrogliosis  IMP  RGD 
Atmem1KyoRatmicrogliosis  IMP  RGD 
F344-Atmem1KyoRatmicrogliosis  IMP  RGD 
AtmRatoxidative stress  IMP DNA:deletion:exon:RGD 
Atmem1KyoRatoxidative stress  IMP  RGD 
F344-Atmem1KyoRatoxidative stress  IMP  RGD 
Objects Annotated

Genes (Rattus norvegicus)
Atm  (ATM serine/threonine kinase)
Atmem1Kyo  (ATM serine/threonine kinase; ZFN induced mutant 1, Kyo)
Atmm1Kyo  (ATM serine/threonine kinase; ENU induced mutant 1, Kyo)

Genes (Mus musculus)
Atm  (ataxia telangiectasia mutated)

Genes (Homo sapiens)
ATM  (ATM serine/threonine kinase)

Strains
F344-Atmem1Kyo  (ZFN-Atm rats)
F344-Atmm1Kyo  (Atm missense rats)


Additional Information