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 () 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 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.-mutant rats ( ) expressed low levels of ATM protein, suggesting a destabilizing effect of the mutation, and had a significantly reduced lifespan compared with 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 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 mutant rat as hind-limb paralysis. This mutant represents a useful model to investigate the importance of neuroinflammation in A-T.

SMG1 heterozygosity exacerbates haematopoietic cancer development in Atm null mice by increasing persistent DNA damage and oxidative stress

“…Long‐term unrepaired DNA damage results in accumulation of DNA in the cytoplasm of cells which activates the cGAS/STING pathway to induce interferon (IFN) production . This has previously been demonstrated in bone marrow‐derived cells from Atm −/− mice and in isolated cells and tissues from rats lacking ATM expression . However, in tissues analysed here IFNβ was barely detected in any Atm −/− Smg1 gt/+ mice (Figure D).…”

“…Atm knockout (−/−) mice are prone to the development of thymic lymphomas, are radiosensitive and show evidence of oxidative damage to tissues . Furthermore, loss of ATM and the resultant accumulation of unrepaired DNA damage can lead to activation of innate immune pathways and basal inflammation . SMG1 has a well‐characterized role in nonsense‐mediated decay (NMD), the pathway used by cells to detect and degrade mRNA with premature termination codons which may code for truncated proteins .…”

PIKKing a way to regulate inflammation

“…This process was exacerbated by irradiation. Our work has further shown that this autoinflammatory process occurs in both glia and neurons in the brain and spinal cord of Atm − / − rats and also that there is activation of the NF‐κB signaling pathway and upregulation of IL‐1β . Whether inflammasomes are also activated in response to this build‐up of cytoplasmic DNA is under investigation.…”

“…For example, loss of ATM has long been known to lead to the accumulation of unrepaired DNA damage but recent studies have shown that this DNA damage can lead to a build‐up of DNA in the cytoplasm of cells leading to inflammation . Our work has shown that this process can occur in neurons in an animal model of the disease ataxia‐telangiectasia and that targeting the induced inflammation can limit disease progression . This review will examine the family members and what is known about their roles in inflammation and consequent disease.…”

Neurodegeneration in ataxia‐telangiectasia: Multiple roles of ATM kinase in cellular homeostasis

“…The recently described Atm knockout rat model does not display cerebellar atrophy, however spinal cord atrophy and paralysis were observed (Quek et al, ; Quek et al, ). There was significant loss of motor neurons and activation of microglia in the spinal cord, consistent with a neuroinflammatory phenotype.…”