Inactive Atm abrogates DSB repair in mouse cerebellum more than does Atm loss, without causing a neurological phenotype

Tal, Efrat; Alfo, Marina; Zha, Shan; Barzilai, Ari; Zeeuw, Chris I. De; Ziv, Yael; Shiloh, Yosef

doi:10.1016/j.dnarep.2018.10.001

Cited by 16 publications

(10 citation statements)

References 85 publications

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“…A major factor limiting our ability to define why loss of DDR proteins, like ATM, selectively impacts the cerebellum and causes progressive ataxia is the lack of an animal model that recapitulates these neurological symptoms (Lavin 2013). Several A-T rodent models have been created over the past several years by inserting gene mutations that cause protein dysfunction (lack kinase activity) or complete deficiency (Herzog et al 1998;Xu and Baltimore 1996;Elson et al 1996;Spring et al 2001;Campbell et al 2015;Quek et al 2016;Tal et al 2018;Lavin 2013); a minipig was also recently reported (Beraldi et al 2017). However, none develop an overt, progressive ataxia with cerebellar dysfunction and atrophy that recapitulates the human disease, even though other aspects of the disorder like thyroid cancers, infertility, and immune abnormalities do develop.…”

Section: Introductionmentioning

confidence: 99%

A novel, ataxic mouse model of ataxia telangiectasia caused by a clinically relevant nonsense mutation

Perez

Abdallah

Chavira

et al. 2021

eLife

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Ataxia Telangiectasia (A-T) and Ataxia with Ocular Apraxia Type 1 (AOA1) are devastating neurological disorders caused by null mutations in the genome stability genes, A-T mutated (ATM) and Aprataxin (APTX), respectively. Our mechanistic understanding and therapeutic repertoire for treating these disorders are severely lacking, in large part due to the failure of prior animal models with similar null mutations to recapitulate the characteristic loss of motor coordination (i.e., ataxia) and associated cerebellar defects. By increasing genotoxic stress through the insertion of null mutations in both the Atm (nonsense) and Aptx (knockout) genes in the same animal, we have generated a novel mouse model that for the first time develops a progressively severe ataxic phenotype associated with atrophy of the cerebellar molecular layer. We find biophysical properties of cerebellar Purkinje neurons (PNs) are significantly perturbed (e.g., reduced membrane capacitance, lower action potential [AP] thresholds, etc.), while properties of synaptic inputs remain largely unchanged. These perturbations significantly alter PN neural activity, including a progressive reduction in spontaneous AP firing frequency that correlates with both cerebellar atrophy and ataxia over the animal’s first year of life. Double mutant mice also exhibit a high predisposition to developing cancer (thymomas) and immune abnormalities (impaired early thymocyte development and T-cell maturation), symptoms characteristic of A-T. Finally, by inserting a clinically relevant nonsense-type null mutation in Atm, we demonstrate that Small Molecule Read-Through (SMRT) compounds can restore ATM production, indicating their potential as a future A-T therapeutic.

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Section: Introductionmentioning

confidence: 99%

A novel, ataxic mouse model of ataxia telangiectasia caused by a clinically relevant nonsense mutation

Perez

Abdallah

Chavira

et al. 2021

eLife

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“…In contrast, in human ATM KO microglia, we failed to observe global damage of ATM-deficient neurons via secretion. One possibility is that the long-term use of an ATM inhibitor, which acts as a dominant negative mutant of ATM (59), exacerbated the toxicity of murine microglia and contributed to neuronal susceptibility to inflammation. In the present work, the levels of phagocytosis of both damaged and live neuronal material by ATM KO microglia were on average 40-50% higher compared to WT cells.…”

Section: Discussionmentioning

confidence: 99%

Persistent DNA damage promotes microglial dysfunction in Ataxia-telangiectasia

Bourseguin

Cheng

Talbot

et al. 2021

Preprint

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The autosomal recessive genome instability disorder Ataxia-telangiectasia, caused by mutations in ATM kinase, is characterised by the progressive loss of cerebellar neurons. We find that DNA damage associated with ATM loss results in dysfunctional behaviour of human microglia, immune cells of the central nervous system. Microglial dysfunction is mediated by the pro-inflammatory RELB/p52 non-canonical NF-κB transcriptional pathway and leads to excessive phagocytic clearance of neurites. Pathological phagocytosis of neuronal processes by microglia has also been observed in multiple sclerosis, Alzheimer′s and progranulin deficiency, suggesting a common mechanism that promotes neuronal damage. Activation of the RELB/p52 pathway in ATM-deficient microglia is driven by persistent DNA damage and is dependent on the NIK kinase. These results provide insights into the underlying mechanisms of aberrant microglial behaviour in Ataxia telangiectasia, potentially contributing to neurodegeneration.

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“…The most frequent mutations in A-T patients lead to protein truncation and instability or to protein with poor kinase activity, and very few patients have been reported to express an ATM-KD protein, suggesting a negative selective pressure on fixing this type of mutation. Conditional expression of ATM-KD in the murine nervous system showed a more pronounced neurological phenotype than ATM loss with accumulation of DSBs in cultured nervous cells and in Purkinje cells in the cerebellum [ 67 ]. Tumorigenesis was studied in mice completely lacking ATM or carrying an inactive form of the protein.…”

Section: Lessons From Mouse Models: Atm Knockout and Atm Kinase Deadmentioning

confidence: 99%

ATM Kinase Dead: From Ataxia Telangiectasia Syndrome to Cancer

Putti

Giovinazzo

Merolle

et al. 2021

Cancers

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ATM is one of the principal players of the DNA damage response. This protein exerts its role in DNA repair during cell cycle replication, oxidative stress, and DNA damage from endogenous events or exogenous agents. When is activated, ATM phosphorylates multiple substrates that participate in DNA repair, through its phosphoinositide 3-kinase like domain at the 3′end of the protein. The absence of ATM is the cause of a rare autosomal recessive disorder called Ataxia Telangiectasia characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility, and radiation sensitivity. There is a correlation between the severity of the phenotype and the mutations, depending on the residual activity of the protein. The analysis of patient mutations and mouse models revealed that the presence of inactive ATM, named ATM kinase-dead, is more cancer prone and lethal than its absence. ATM mutations fall into the whole gene sequence, and it is very difficult to predict the resulting effects, except for some frequent mutations. In this regard, is necessary to characterize the mutated protein to assess if it is stable and maintains some residual kinase activity. Moreover, the whole-genome sequencing of cancer patients with somatic or germline mutations has highlighted a high percentage of ATM mutations in the phosphoinositide 3-kinase domain, mostly in cancer cells resistant to classical therapy. The relevant differences between the complete absence of ATM and the presence of the inactive form in in vitro and in vivo models need to be explored in more detail to predict cancer predisposition of A-T patients and to discover new therapies for ATM-associated cancer cells. In this review, we summarize the multiple discoveries from humans and mouse models on ATM mutations, focusing into the inactive versus null ATM.

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Inactive Atm abrogates DSB repair in mouse cerebellum more than does Atm loss, without causing a neurological phenotype

Cited by 16 publications

References 85 publications

A novel, ataxic mouse model of ataxia telangiectasia caused by a clinically relevant nonsense mutation

A novel, ataxic mouse model of ataxia telangiectasia caused by a clinically relevant nonsense mutation

Persistent DNA damage promotes microglial dysfunction in Ataxia-telangiectasia

ATM Kinase Dead: From Ataxia Telangiectasia Syndrome to Cancer

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