Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-β
Elsa Suberbielle,Pascal E. Sanchez,Alexxai V. Kravitz,Xin Wang,Kaitlyn Ho,Kirsten Eilertson,Nino Devidze,Anatol C. Kreitzer,Lennart Mucke +8 more
TLDR
In this paper, the authors show that a natural behavior, exploration of a novel environment, causes DNA double-strand breaks (DSBs) in neurons of young adult wild-type mice.Abstract:
We show that a natural behavior, exploration of a novel environment, causes DNA double-strand breaks (DSBs) in neurons of young adult wild-type mice. DSBs occurred in multiple brain regions, were most abundant in the dentate gyrus, which is involved in learning and memory, and were repaired within 24 h. Increasing neuronal activity by sensory or optogenetic stimulation increased neuronal DSBs in relevant but not irrelevant networks. Mice transgenic for human amyloid precursor protein (hAPP), which simulate key aspects of Alzheimer's disease, had increased neuronal DSBs at baseline and more severe and prolonged DSBs after exploration. Interventions that suppress aberrant neuronal activity and improve learning and memory in hAPP mice normalized their levels of DSBs. Blocking extrasynaptic NMDA-type glutamate receptors prevented amyloid-β (Aβ)-induced DSBs in neuronal cultures. Thus, transient increases in neuronal DSBs occur as a result of physiological brain activity, and Aβ exacerbates DNA damage, most likely by eliciting synaptic dysfunction.read more
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Optogenetics: 10 years of microbial opsins in neuroscience
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Network abnormalities and interneuron dysfunction in Alzheimer disease
Jorge J. Palop,Lennart Mucke +1 more
TL;DR: The concept that modulating these mechanisms may help to improve brain function in Alzheimer disease and related disorders is explored.
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Sources of DNA Double-Strand Breaks and Models of Recombinational DNA Repair
Anuja Mehta,James E. Haber +1 more
TL;DR: In this paper, the authors highlight the chief sources of double-strand break (DSB) and crucial requirements for each of these repair processes, as well as the methods to identify and study intermediate steps in DSB repair by homologous recombination.
Journal ArticleDOI
Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes
Ram Madabhushi,Fan Gao,Andreas R. Pfenning,Ling Pan,Satoko Yamakawa,Jinsoo Seo,Richard Rueda,Trongha X. Phan,Hidekuni Yamakawa,Ping-Chieh Pao,Ryan T. Stott,Elizabeta Gjoneska,Alexi Nott,Sukhee Cho,Manolis Kellis,Manolis Kellis,Li-Huei Tsai,Li-Huei Tsai +17 more
TL;DR: It is reported that neuronal activity stimulation triggers the formation of DNA double strand breaks (DSBs) in the promoters of a subset of early-response genes, including Fos, Npas4, and Egr1.
Journal ArticleDOI
Mosaic Copy Number Variation in Human Neurons
Michael J. McConnell,Michael R. Lindberg,Kristen J. Brennand,Julia C. Piper,Thierry Voet,Thierry Voet,Chris Cowing-Zitron,Svetlana Shumilina,Roger S. Lasken,Roger S. Lasken,Joris Vermeesch,Ira M. Hall,Fred H. Gage +12 more
TL;DR: Single-cell sequencing of endogenous human frontal cortex neurons revealed that 13 to 41% of neurons have at least one megabase-scale de novo CNV, that deletions are twice as common as duplications, and that a subset of neurons has highly aberrant genomes marked by multiple alterations.
References
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Jorge J. Palop,Lennart Mucke +1 more
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