Reduced Synchronization Persistence in Neural Networks Derived from Atm-Deficient Mice

Levine-Small, Noah; Yekutieli, Ziv; Aljadeff, Johnatan; Boccaletti, Stefano; Ben‐Jacob, Eshel; Barzilai, Ari

doi:10.3389/fnins.2011.00046

Cited by 13 publications

(4 citation statements)

References 51 publications

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“…DNA-damaging agents [48,72]. A knock-in mouse model expressing a mutant form of Atm, corresponding to a common patient mutation [7636del9, resulting in the loss of 3 amino acid residues (serine, arginine, isoleucine; 2556-2558)], had a significantly longer lifespan than Atm 2/2 mice when maintained under nonspecific, pathogen-free conditions, which could be accounted for by a lower incidence of thymic lymphomas and extensive apoptosis in these lymphomas [73].…”

Section: Discussionmentioning

confidence: 99%

Rats with a missense mutation in Atm display neuroinflammation and neurodegeneration subsequent to accumulation of cytosolic DNA following unrepaired DNA damage

Quek

Luff

Cheung

et al. 2016

Journal of Leukocyte Biology

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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.

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Section: Discussionmentioning

confidence: 99%

Rats with a missense mutation in Atm display neuroinflammation and neurodegeneration subsequent to accumulation of cytosolic DNA following unrepaired DNA damage

Quek

Luff

Cheung

et al. 2016

Journal of Leukocyte Biology

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“…Based on our previous results (Dar et al 2006(Dar et al , 2011Levine-Small et al 2011), we hypothesized that malfunctioning DDR is the main cause for neuronal degeneration in genomic instability disorders including A-T. However, Atm-deficient mice display very mild cerebellar defects but exhibit severe age-dependent degeneration of tyrosine hydroxylase-positive, dopaminergic nigro-striatal neurons (Eilam et al 1998(Eilam et al , 2003.…”

Section: Resultsmentioning

confidence: 96%

Malfunctioning DNA Damage Response (DDR) Leads to the Degeneration of Nigro-Striatal Pathway in Mouse Brain

et al. 2011

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Pronounced neuropathology is a feature of ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome (NBS), which are both genomic instability syndromes. The Nbs1 protein, which is defective in NBS, is a component of the Mre11/RAD50/NBS1 (MRN) complex. This complex plays a major role in the early phase of the cellular response to double strand breaks (DSBs) in the DNA. Among others, MRN is required for timely activation of the protein kinase ATM (A-T mutated), which is disrupted in patients with A-T. Earlier reports show that Atm-deficient mice exhibit severe degeneration of tyrosine hydroxylase (TH)-positive dopaminergic nigro-striatal neurons and their terminals in the striatum. This cell loss is accompanied by a large reduction in immunoreactivity for the dopamine transporter protein (DAT) in the striatum. To test whether Nbs1 inactivation also affects the integrity of the nigro-striatal pathway, we examined this pathway in a murine model with conditional inactivation of the Nbs1 gene in central nervous system (Nbs1-CNS-Δ). We report that this model has a reduction in TH-positive cells in the substantia nigra. This phenomenon was seen at very early age, while Atm-/- mice showed a progressive age-dependent reduction. Furthermore, we observed an age-dependent increase in the level of TH in the striatum of Atm-/- and Nbs1-CNS-Δ mice. In addition to the altered expression of TH, we also found a reduction of DAT in the striatum of both Atm-/- and Nbs1-CNS-Δ mice at 60 days of age. Finally, microglial recruitment and alterations in the levels of various neurotrophic factors were also observed. These results indicate that malfunctioning DNA damage response severely affects the integrity of the nigro-striatal pathway and suggest a new neurodegenerative pathway in Parkinsonian syndromes.

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“…Many BDDs are characterized by malfunctioning DDR, and it is important to understand how malfunctioning DDR influences the dynamics of neural-glial networks. Using microelectrode arrays to simultaneously record data from many neurons, Levine-Small et al [40] analyzed how ATM deficiency affected the dynamics of neural-glial networks. Interestingly, no differences in firing activity between individual wild-type and ATM-deficient neurons were detected in response to DNA damage.…”

Section: Malfunctioning Ddr Affects Brain Functionalitymentioning

confidence: 99%

Connecting Malfunctioning Glial Cells and Brain Degenerative Disorders

Kaminsky

Bihari

Kanner

et al. 2016

Genomics, Proteomics &Amp; Bioinformatics

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The DNA damage response (DDR) is a complex biological system activated by different types of DNA damage. Mutations in certain components of the DDR machinery can lead to genomic instability disorders that culminate in tissue degeneration, premature aging, and various types of cancers. Intriguingly, malfunctioning DDR plays a role in the etiology of late onset brain degenerative disorders such as Parkinson’s, Alzheimer’s, and Huntington’s diseases. For many years, brain degenerative disorders were thought to result from aberrant neural death. Here we discuss the evidence that supports our novel hypothesis that brain degenerative diseases involve dysfunction of glial cells (astrocytes, microglia, and oligodendrocytes). Impairment in the functionality of glial cells results in pathological neuro-glial interactions that, in turn, generate a “hostile” environment that impairs the functionality of neuronal cells. These events can lead to systematic neural demise on a scale that appears to be proportional to the severity of the neurological deficit.

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Reduced Synchronization Persistence in Neural Networks Derived from Atm-Deficient Mice

Cited by 13 publications

References 51 publications

Rats with a missense mutation in Atm display neuroinflammation and neurodegeneration subsequent to accumulation of cytosolic DNA following unrepaired DNA damage

Rats with a missense mutation in Atm display neuroinflammation and neurodegeneration subsequent to accumulation of cytosolic DNA following unrepaired DNA damage

Malfunctioning DNA Damage Response (DDR) Leads to the Degeneration of Nigro-Striatal Pathway in Mouse Brain

Connecting Malfunctioning Glial Cells and Brain Degenerative Disorders

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