ATM-deficient human neural stem cells as an in vitro model system to study neurodegeneration

Carlessi, Luigi; Poli, Elena Fusar; Filippis, Lidia De; Delia, Domenico

doi:10.1016/j.dnarep.2013.04.013

Cited by 20 publications

(19 citation statements)

References 48 publications

(31 reference statements)

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“…Indeed, OPC derived from Nbs1-CNS -Δ −/− or Atm −/− failed to differentiate into mature OL in culture (Allen et al, 2001; Carlessi et al, 2009; Carlessi et al, 2013; Liu et al, 2014b). In vivo, as early as seven days postnatal, the number of proliferating OPC is significantly reduced and apoptotic OPC increased in the Nbs1-CNS -Δ −/− brain with a resulting loss of myelin proteins including MBP, MOG and PLP in the corpus callosum (Liu et al, 2014a, b).…”

Section: Oligodendrocytes and Myelin Are Vulnerable To Genetic Defmentioning

confidence: 99%

“…Left panel HDAC1/2 and ATM are recruited to the DNA lesions to facilitate NMEJs in age-associated DSBs (Lee and Paull, 2005; Miller et al, 2010). But HDAC1/2 and ATM are also known to promote OL maturation by promoting myelin gene expression (Shen et al, 2008a; Shen et al, 2008b), and OPC differentiation respectively (Allen et al, 2001; Carlessi et al, 2009; Carlessi et al, 2013; Liu et al, 2014b). ATM may affect MyRF expression but the underlying molecular mechanism remains unknown (Liu et al, 2014b).…”

Section: Aging Ols and Their Lineage-specific Dependence On Componmentioning

confidence: 99%

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DNA damage in the oligodendrocyte lineage and its role in brain aging

Tse

Herrup

2017

Mechanisms of Ageing and Development

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Myelination is a recent evolutionary addition that significantly enhances the speed of transmission in the neural network. Even slight defects in myelin integrity impair performance and enhance the risk of neurological disorders. Indeed, myelin degeneration is an early and well-recognized neuropathology that is age associated, but appears before cognitive decline. Myelin is only formed by fully differentiated oligodendrocytes, but the entire oligodendrocyte lineage are clear targets of the altered chemistry of the aging brain. As in neurons, unrepaired DNA damage accumulates in the postmitotic oligodendrocyte genome during normal aging, and indeed may be one of the upstream causes of cellular aging - a fact well illustrated by myelin co-morbidity in premature aging syndromes arising from deficits in DNA repair enzymes. The clinical and experimental evidence from Alzheimer's disease, progeroid syndromes, ataxia-telangiectasia and other conditions strongly suggest that oligodendrocytes may in fact be uniquely vulnerable to oxidative DNA damage. If this damage remains unrepaired, as is increasingly true in the aging brain, myelin gene transcription and oligodendrocyte differentiation is impaired. Delineating the relationships between early myelin loss and DNA damage in brain aging will offer an additional dimension outside the neurocentric view of neurodegenerative disease.

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Section: Oligodendrocytes and Myelin Are Vulnerable To Genetic Defmentioning

confidence: 99%

Section: Aging Ols and Their Lineage-specific Dependence On Componmentioning

confidence: 99%

DNA damage in the oligodendrocyte lineage and its role in brain aging

Tse

Herrup

2017

Mechanisms of Ageing and Development

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“…Neurological manifestations presented by AT patients resulted from cerebellar atrophy (Carlessi et al. 2013). Neurodegeneration of the cerebellum is progressive and is responsible for unsteady gait, poor muscle control, abnormal eye movements and problems with speaking or swallowing (McKinnon 2004).…”

Section: Introductionmentioning

confidence: 99%

Ten new ATM alterations in Polish patients with ataxia‐telangiectasia

Podralska

Stembalska

Ślężak

et al. 2014

Molec Gen & Gen Med

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Inherited biallelic mutations of the ATM gene are responsible for the development of ataxia telangiectasia (AT). The objective of the present study was to conduct molecular analysis of the ATM gene in a cohort of 24 Polish patients with ataxia-telangiectasia with aim being to provide an updated mutational spectrum in Polish AT patients. As a result of molecular analysis, the status of recurrent mutation was confirmed and ten new ATM variants were detected. Application of MLPA analysis allowed the detection of large genomic deletion. Previously, this type of mutation had never been seen in our population. Finally, in silico analysis was carried out for newly detected ATM alterations. In addition, functional analysis was performed to evaluate the effects of intronic variants: c.3402+30_3402+32delATC.

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“…This was, to the best of our knowledge and at the time of writing the first exemplification of an iPS cell derived neuronal model of A-T. However this has recently changed [196,212].…”

Section: Discussionmentioning

confidence: 99%

“…These included aberrant regulation of glutamate receptor signaling, CREB signaling and axonal guidance pathways. Interestingly, Carlessi et al [212] showed neuronal differentiation bias after ATM knockdown with neuronal progenitors consistently producing fewer GABAergic neurons. Although we did not quantify the ratios of GLUTAmatergic to GABAergic neurons, the fact that we observe extensive upregulation of genes involved with glutamate receptor signaling may support the notion that such a bias also exists in our cultures.…”

Section: Discussionmentioning

confidence: 99%

Induced pluripotent stem cells from patients with ataxia-telangiectasia

Nayler¹

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A-T (Ataxia-Telangiectasia) is a multi-systemic, rare genetic disorder hallmarked by predisposition to cancer, immune deficiency and most notably progressive neurodegeneration [1]. A-T results from mutation of the ATM gene (11q22.3). ATM is a protein kinase belonging to the phosphatidylinositol 3-kinase-like family [2]. ATM exerts control over genomic integrity by recognizing and responding to DNA damage, through phosphorylation of substrates involved in cell cycle control and DNA damage repair [1]. The ATM protein is involved with numerous cellular processes and as such, A-T represents a paradigm for neurodegenerative disorders, as well as cancer.Experimental models of ATM function have been restricted to systems of limited context to understanding ATM biology and its potential role in development and tissue formation.Animal models have failed to faithfully recapitulate the full spectrum of A-T symptoms including the neurodegenerative aspect, which remains poorly understood. To date, studies on A-T have failed to answer the fundamental question of why certain cell types are seemingly more affected than others. As access to pluripotent stem cells becomes mainstream, it becomes possible, to a degree, to recreate and study in vitro processes giving rise to various cell types, including neurons, using directed differentiation protocols.We hypothesized that ATM deficient cells may be difficult or impossible to reprogram without intervention or assistance, and that this difficulty may be at least in part due excessive levels of reprogramming-induced or existing DNA damage, to the poor growth characteristics of A-T cells or the inability to participate in certain pathways necessary for reprogramming. We show that it was indeed possible to generate iPSCs from A-T patients albeit at reduced efficiency. This thesis describes the first generation and characterization of bona fide iPS cells from patients with A-T. Additionally we use this model system to explore the role and functionality of ATM in an embryonic setting, showing that ATM signaling is vitally required for the maintenance of cell cycle control and DNA fidelity after DNA damage. We have defined the transcriptional landscape of pluripotent stem cells from patients with A-T and point to novel findings regarding oxidative phosphorylation pathways. Further to this, we have used this model system to explore the role of ATM in neurogenesis and neuronal activity. We provide evidence that fosters support for the theory that A-T involves aspects of mitochondrial dysfunction and explore whether calcium trafficking is defective in neurons generated from patient iPSCs. Importantly we have illustrated the proof of concept that genetic manipulation of neuronal cells is possible by delivery of full length ATM, which also restored a functional DNA damage response.Finally, we utilized a neuronal differentiation protocol to generate neural progenitors characteristic of the developing cerebellum, and describe the transcriptome of these cells in the absence of ATM. These ...

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ATM-deficient human neural stem cells as an in vitro model system to study neurodegeneration

Cited by 20 publications

References 48 publications

DNA damage in the oligodendrocyte lineage and its role in brain aging

DNA damage in the oligodendrocyte lineage and its role in brain aging

Ten new ATM alterations in Polish patients with ataxia‐telangiectasia

Induced pluripotent stem cells from patients with ataxia-telangiectasia

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