Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-β

Suberbielle, Elsa; Sanchez, Pascal; Kravitz, Alexxai V.; Wang, Xin; Ho, Kaitlyn; Eilertson, Kirsten; Devidze, Nino; Kreitzer, Anatol C.; Mucke, Lennart

doi:10.1038/nn.3356

Cited by 410 publications

(533 citation statements)

References 56 publications

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“…We therefore crossed hTau‐A152T (L1) mice and hTau‐WT (L32) mice with hAPP transgenic mice from line J20 (hAPP‐J20) (Fig 11A–D). hAPP‐J20 mice have pathologically elevated levels of human Aβ in the brain, increased risk of early death (most likely from epileptic activity), and AD‐like features, including memory problems, behavioral alterations, synaptic impairments, amyloid plaques, neuritic dystrophy, astrocytosis, and microgliosis 49, 50, 51, 52, 53.…”

Section: Resultsmentioning

confidence: 99%

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

et al. 2016

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A152T‐variant human tau (hTau‐A152T) increases risk for tauopathies, including Alzheimer's disease. Comparing mice with regulatable expression of hTau‐A152T or wild‐type hTau (hTau‐WT), we find age‐dependent neuronal loss, cognitive impairments, and spontaneous nonconvulsive epileptiform activity primarily in hTau‐A152T mice. However, overexpression of either hTau species enhances neuronal responses to electrical stimulation of synaptic inputs and to an epileptogenic chemical. hTau‐A152T mice have higher hTau protein/mRNA ratios in brain, suggesting that A152T increases production or decreases clearance of hTau protein. Despite their functional abnormalities, aging hTau‐A152T mice show no evidence for accumulation of insoluble tau aggregates, suggesting that their dysfunctions are caused by soluble tau. In human amyloid precursor protein (hAPP) transgenic mice, co‐expression of hTau‐A152T enhances risk of early death and epileptic activity, suggesting copathogenic interactions between hTau‐A152T and amyloid‐β peptides or other hAPP metabolites. Thus, the A152T substitution may augment risk for neurodegenerative diseases by increasing hTau protein levels, promoting network hyperexcitability, and synergizing with the adverse effects of other pathogenic factors.

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Section: Resultsmentioning

confidence: 99%

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

et al. 2016

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“…The DNA damage response Surprisingly, double-strand breaks in DNA can result simply from normal physiological behaviour, such as exploration of a novel environment [100]. Most recently, Madabhushi et al [101] have shown that neuronal activity results in double-strand DNA breaks in promoters that enhance expression of early response genes.…”

Section: Cell Stressmentioning

confidence: 99%

The increasing diversity of functions attributed to the SAFB family of RNA-/DNA-binding proteins

Norman

Rivers

Lee

et al. 2016

Biochemical Journal

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RNA-binding proteins play a central role in cellular metabolism by orchestrating the complex interactions of coding, structural and regulatory RNA species. The SAFB (scaffold attachment factor B) proteins (SAFB1, SAFB2 and SAFB-like transcriptional modulator, SLTM), which are highly conserved evolutionarily, were first identified on the basis of their ability to bind scaffold attachment region DNA elements, but attention has subsequently shifted to their RNA-binding and protein-protein interactions. Initial studies identified the involvement of these proteins in the cellular stress response and other aspects of gene regulation. More recently, the multifunctional capabilities of SAFB proteins have shown that they play crucial roles in DNA repair, processing of mRNA and regulatory RNA, as well as in interaction with chromatin-modifying complexes. With the advent of new techniques for identifying RNA-binding sites, enumeration of individual RNA targets has now begun. This review aims to summarise what is currently known about the functions of SAFB proteins.

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“…Moreover, new types of epigenetic modifications on DNA and histone variants are still being identified in the brain (129,130). In particular, evidence indicate a critical interplay between the different epigenetic modifications for the control of learning and memory processes, defining an epigenetic code for learning and memory, underlying the difficulty to study isolated modifications and their consequences.…”

Section: Discussionmentioning

confidence: 99%

Histone acetylation in neuronal (dys)function

Bonnaud¹,

Suberbielle²,

Malnou³

2016

Biomolecular Concepts

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Abstract:Cognitive functions require the expression of an appropriate pattern of genes in response to environmental stimuli. Over the last years, many studies have accumulated knowledge towards the understanding of molecular mechanisms that regulate neuronal gene expression. Epigenetic modifications have been shown to play an important role in numerous neuronal functions, from synaptic plasticity to learning and memory. In particular, histone acetylation is a central player in these processes. In this review, we present the molecular mechanisms of histone acetylation and summarize the data underlying the relevance of histone acetylation in cognitive functions in normal and pathological conditions. In the last part, we discuss the different mechanisms underlying the dysregulation of histone acetylation associated with neurological disorders, with a particular focus on environmental causes (stress, drugs, or infectious agents) that are linked to impaired histone acetylation.

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Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-β

Cited by 410 publications

References 56 publications

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

The increasing diversity of functions attributed to the SAFB family of RNA-/DNA-binding proteins

Histone acetylation in neuronal (dys)function

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