Ataxia telangiectasia mutated is essential during adult neurogenesis

Allen, Duane M.; Praag, Henriette van; Ray, Jasodhara; Weaver, Zoë; Winrow, Christopher J.; Carter, Todd A.; Braquet, Ray; Harrington, Elizabeth A.; Ried, Thomas; Brown, Kevin D.; Gage, Fred H.; Barlow, Carrolee

doi:10.1101/gad.869001

Cited by 149 publications

(139 citation statements)

References 46 publications

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“…These results suggest that in neuronal cells, replication compartment formation is impaired, and HSV-1 is unable to cause a DNA damage response. This finding is consistent with reports that neurons are inefficient at DNA repair (38,39) and that ATM is specifically down-regulated when neuronal precursors are differentiated to a neuronal lineage (40). The cellular transcription factor Oct-1 is required for efficient assembly of HSV-1 replication compartments (41).…”

Section: Viral Replication and Growth Are Greater In The Presence Of supporting

confidence: 81%

DNA repair proteins affect the lifecycle of herpes simplex virus 1

Lilley

Carson²,

Muotri³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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223

344

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We report that herpes simplex virus 1 (HSV-1) infection can activate and exploit a cellular DNA damage response that aids viral replication in nonneuronal cells. Early in HSV-1 infection, several members of the cellular DNA damage-sensing machinery are activated and accumulate at sites of viral DNA replication. When this cellular response is abrogated, formation of HSV-1 replication centers is retarded, and viral production is compromised. In neurons, HSV-1 replication centers fail to mature, and the DNA damage response is not initiated. These data suggest that the failure of neurons to mount a DNA damage response to HSV-1 may contribute to the establishment of latency.replication ͉ Mre11 ͉ damage ͉ signaling ͉ ataxia telangiectasia mutated

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Section: Viral Replication and Growth Are Greater In The Presence Of supporting

confidence: 81%

DNA repair proteins affect the lifecycle of herpes simplex virus 1

Lilley

Carson²,

Muotri³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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223

344

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“…These findings concur with subtle neurological abnormalities reported previously, including electrophysiological deficiencies. 15,22,46,[72][73][74][75][76][77] The symptomatic picture presented in A-T patients is complex and multifaceted, partly progressive, and occasionally fixed over a limited period of time. The diversity of systems affected by the disease and their interconnections makes it difficult to determine which of the disease manifestations is primary and which reflects added systemic complications.…”

Section: Discussionmentioning

confidence: 99%

A Role for Vascular Deficiency in Retinal Pathology in a Mouse Model of Ataxia-Telangiectasia

Raz-Prag

Galron

Segev-Amzaleg

et al. 2011

The American Journal of Pathology

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Ataxia-telangiectasia is a multifaceted syndrome caused by null mutations in the ATM gene, which encodes the protein kinase ATM, a key participant in the DNA damage response. Retinal neurons are highly susceptible to DNA damage because they are terminally differentiated and have the highest metabolic activity in the central nervous system. In this study, we characterized the retina in young and aged Atmdeficient mice (Atm ؊/؊ ). At 2 months of age, angiography revealed faint retinal vasculature in Atm ؊/؊ animals relative to wild-type controls. This finding was accompanied by increased expression of vascular endothelial growth factor protein and mRNA. Fibrinogen, generally absent from wild-type retinal tissue, was evident in Atm ؊/؊ retinas, whereas mRNA of the tight junction protein occludin was significantly decreased. Immunohistochemistry labeling for occludin in 6-month-old mice showed that this decrease persists in advanced stages of the disease. Some brain disorders may have a vascular origin, 1,2 and vascular diseases can be directly linked to neuronal and synaptic dysfunction through changes in the blood flow, increase in blood-brain barrier permeability, and in nutrient supply. 3 A healthy brain relies on the proper function and communication of all cells comprising the neurovascular unit: neurons, astrocytes, brain endothelium, and vascular smooth muscle cells. 4 Impaired genomic stability interferes with cellular homeostasis and poses a constant threat to cellular viability. 5 The cell combats this threat by activating the DNA damage response (DDR), a complex signaling network that detects the DNA lesions, promotes their repair, and temporarily modulates cellular metabolism while the damage is being repaired. 6 The DDR is vigorously activated by DNA double-strand breaks (DSBs), a particularly cytotoxic DNA lesion induced by ionizing radiation, radiomimetic chemicals, and oxygen radicals. 7,8 The DNA damage response is a hierarchical process executed by sensor/mediator proteins that accumulate at DSB sites and by protein kinases that serve as transducers of the DNA damage alarm to numerous downstream effectors. 6 The primary transducer of the cellular response to DSBs is the protein kinase ATM, which phosphorylates many key players in the various branches of the DDR. 9 Ataxia-telangiectasia (A-T) is an autosomal recessive disorder caused by mutations in the ATM gene that encodes the ATM protein. 10 A-T is characterized by progressive neurodegeneration affecting mainly the cerebellum, which develops into severe neuromotor dysfunction;

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“…32 An earlier work with ATMÀ/À animals has shown an essential role for ATM in adult neurogenesis and neuronal survival in vivo and in vitro. 33 Accordingly, ATMÀ/À mice show a reduced number of neural progenitors that proliferate and survive in response to running stress compared with wild type mice, and furthermore, ATMÀ/À neural progenitors in vitro are unable to differentiate into oligodendrocytes or neurons, though capable of differentiating into astrocytes. These findings obtained with murine cells concord with our results as regards the effects of ATM deficiency on oligodendrocytes, but not neurons.…”

Section: Discussionmentioning

confidence: 99%

DNA-damage response, survival and differentiation in vitro of a human neural stem cell line in relation to ATM expression

et al. 2009

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Ataxia-telangiectasia (A-T) is a neurodegenerative disorder caused by defects in the ATM kinase, a component of the DNA-damage response (DDR). Here, we employed an immortalized human neural stem-cell line (ihNSC) capable of differentiating in vitro into neurons, oligodendrocytes and astrocytes to assess the ATM-dependent response and outcome of ATM ablation. The time-dependent differentiation of ihNSC was accompanied by an upregulation of ATM and DNA-PK, sharp downregulation of ATR and Chk1, transient induction of p53 and by the onset of apoptosis in a fraction of cells. The response to ionizing radiation (IR)-induced DNA lesions was normal, as attested by the phosphorylation of ATM and some of its substrates (e.g., Nbs1, Smc1, Chk2 and p53), and by the kinetics of c-H2AX nuclear foci formation. Depletion in these cells of ATM by shRNA interference (shATM) attenuated the differentiation-associated apoptosis and response to IR, but left unaffected the growth, self-renewal and genomic stability. shATM cells generated a normal number of MAP2/b-tubulin III þ neurons, but a reduced number of GalC þ oligodendrocytes, which were nevertheless more susceptible to oxidative stress. Altogether, these findings highlight the potential of ihNSCs as an in vitro model system to thoroughly assess, besides ATM, the role of DDR genes in neurogenesis and/or neurodegeneration.

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Ataxia telangiectasia mutated is essential during adult neurogenesis

Cited by 149 publications

References 46 publications

DNA repair proteins affect the lifecycle of herpes simplex virus 1

DNA repair proteins affect the lifecycle of herpes simplex virus 1

A Role for Vascular Deficiency in Retinal Pathology in a Mouse Model of Ataxia-Telangiectasia

DNA-damage response, survival and differentiation in vitro of a human neural stem cell line in relation to ATM expression

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