Emerging Perspectives on DNA Double-strand Breaks in Neurodegenerative Diseases

Zhu, Ling-Shuang; Wang, Ding-Qi; Ke, Chao; Liú, Dan

doi:10.2174/1570159x17666190726115623

Cited by 20 publications

(15 citation statements)

References 125 publications

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“…Several studies have reported that DSB is augmented in AD brains 4 , 7 , 31 . First, we analyzed hippocampal slices of human AD brain and non-neurodegenerative disease control brain (Table 1 ) to pursue DSB in the AD brain by immunohistochemistry.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, recent reports demonstrate that DSB accumulates in the hippocampus in the brains of AD patients and AD model mice 7 , 31 , 32 . Aβ-induced oxidative stress or activation of N-methyl-D-aspartate receptors (NMDARs) induces DSB 4 , 9 , 33 . Tau protein is almost exclusively localized to the axon, however, it is also reported to localize in the nucleus to stabilize DNA 34 – 38 .…”

Section: Introductionmentioning

confidence: 99%

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Failure of DNA double-strand break repair by tau mediates Alzheimer’s disease pathology in vitro

et al. 2022

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DNA double-strand break (DSB) is the most severe form of DNA damage and accumulates with age, in which cytoskeletal proteins are polymerized to repair DSB in dividing cells. Since tau is a microtubule-associated protein, we investigate whether DSB is involved in tau pathologies in Alzheimer’s disease (AD). First, immunohistochemistry reveals the frequent coexistence of DSB and phosphorylated tau in the cortex of AD patients. In vitro studies using primary mouse cortical neurons show that non-p-tau accumulates perinuclearly together with the tubulin after DSB induction with etoposide, followed by the accumulation of phosphorylated tau. Moreover, the knockdown of endogenous tau exacerbates DSB in neurons, suggesting the protective role of tau on DNA repair. Interestingly, synergistic exposure of neurons to microtubule disassembly and the DSB strikingly augments aberrant p-tau aggregation and apoptosis. These data suggest that DSB plays a pivotal role in AD-tau pathology and that the failure of DSB repair leads to tauopathy.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Failure of DNA double-strand break repair by tau mediates Alzheimer’s disease pathology in vitro

et al. 2022

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“…The data suggest a strong link between DSBs, cancers, and neurodegenerative disorders, as well as several other diseases [9][10][11]. Genome-wide analysis of genes that are the main targets of DSBs was therefore important, including their roles in different biological processes and associations with diseases.…”

Section: Of 18mentioning

confidence: 99%

“…Next, we searched for possible associations of the genes subjected frequently to breakage with diseases. It was described previously that DSBs can lead to cancers and other diseases [9][10][11]. Nevertheless, the genome-wide identification and analysis of the The top ten Gene Ontology (GO) biological process associations of genes subjected to breakage were determined using Profiler (https://biit.cs.ut.ee/gprofiler/gost, accessed 28 June 2022).…”

Section: Associations Of the Genes That Are Targeted By Dsbs With Dis...mentioning

confidence: 99%

“…Next, we searched for possible associations of the genes subjected frequently to breakage with diseases. It was described previously that DSBs can lead to cancers and other diseases [9][10][11]. Nevertheless, the genome-wide identification and analysis of the corresponding genes affected by DSBs have not been performed yet.…”

Section: Associations Of the Genes That Are Targeted By Dsbs With Dis...mentioning

confidence: 99%

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Genes Possessing the Most Frequent DNA DSBs Are Highly Associated with Development and Cancers, and Essentially Overlap with the rDNA-Contacting Genes

Tchurikov

Alembekov

Klushevskaya

et al. 2022

IJMS

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Double-strand DNA breakes (DSBs) are the most deleterious and widespread examples of DNA damage. They inevitably originate from endogenous mechanisms in the course of transcription, replication, and recombination, as well as from different exogenous factors. If not properly repaired, DSBs result in cell death or diseases. Genome-wide analysis of DSBs has revealed the numerous endogenous DSBs in human chromosomes. However, until now, it has not been clear what kind of genes are preferentially subjected to breakage. We performed a genetic and epigenetic analysis of the most frequent DSBs in HEK293T cells. Here, we show that they predominantly occur in the active genes controlling differentiation, development, and morphogenesis. These genes are highly associated with cancers and other diseases. About one-third of the genes possessing frequent DSBs correspond to rDNA-contacting genes. Our data suggest that a specific set of active genes controlling morphogenesis are the main targets of DNA breakage in human cells, although there is a specific set of silent genes controlling metabolism that also are enriched in DSBs. We detected this enrichment by different activators and repressors of transcription at DSB target sites, as well breakage at promoters. We propose that both active transcription and silencing of genes give a propensity for DNA breakage. These results have implications for medicine and gene therapy.

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Inhibiting the DNA damage response pathway promotes functional recovery after spinal cord injury

Ahmed

Tuxworth

2022

Clinical and Translational Dis

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Ahmed and Tuxworth show that inhibiting the DNA damage response pathway using a small molecule inhibitor of ATM, AZD1390, promotes axon regeneration and functional recovery after spinal cord injury. AZD1390 is orally bioavailable and reaches the central nervous system in sufficient amounts to engage the target protein and hence represents an easy-to-deliver compound to promote recovery of function in spinal cord injured patients.

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Emerging Perspectives on DNA Double-strand Breaks in Neurodegenerative Diseases

Cited by 20 publications

References 125 publications

Failure of DNA double-strand break repair by tau mediates Alzheimer’s disease pathology in vitro

Failure of DNA double-strand break repair by tau mediates Alzheimer’s disease pathology in vitro

Genes Possessing the Most Frequent DNA DSBs Are Highly Associated with Development and Cancers, and Essentially Overlap with the rDNA-Contacting Genes

Inhibiting the DNA damage response pathway promotes functional recovery after spinal cord injury

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