DNA repair factor BRCA1 depletion occurs in Alzheimer brains and impairs cognitive function in mice

Suberbielle, Elsa; Djukic, Biljana; Evans, Mark D.; Kim, Daniel H.; Taneja, Praveen; Wang, Xin; Finucane, Mariel M.; Knox, Joseph A.; Ho, Kaitlyn; Devidze, Nino; Masliah, Eliezer; Mucke, Lennart

doi:10.1038/ncomms9897

Cited by 153 publications

(177 citation statements)

References 70 publications

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“…Supporting this notion are studies on the tumor suppressor BRCA1 that demonstrated that ablation of BRCA1 by Nestin-cre lead to severe brain growth defects [60]. Additionally, silencing of BRCA1 in the adult dentate gyrus leads to a similar behavioral phenotype as we observed in our adult-ablated CCNA2 mice [59]. These studies underscore the importance of the DNA damage response in embryonic neural progenitors as well as in adult neurons.…”

Section: Discussionsupporting

confidence: 80%

Cyclin A2 promotes DNA repair in the brain during both development and aging

Gygli

Chang

Gokozan

et al. 2016

Aging

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Various stem cell niches of the brain have differential requirements for Cyclin A2. Cyclin A2 loss results in marked cerebellar dysmorphia, whereas forebrain growth is retarded during early embryonic development yet achieves normal size at birth. To understand the differential requirements of distinct brain regions for Cyclin A2, we utilized neuroanatomical, transgenic mouse, and mathematical modeling techniques to generate testable hypotheses that provide insight into how Cyclin A2 loss results in compensatory forebrain growth during late embryonic development. Using unbiased measurements of the forebrain stem cell niche, we parameterized a mathematical model whereby logistic growth instructs progenitor cells as to the cell-types of their progeny. Our data was consistent with prior findings that progenitors proliferate along an auto-inhibitory growth curve. The growth retardation in CCNA2-null brains corresponded to cell cycle lengthening, imposing a developmental delay. We hypothesized that Cyclin A2 regulates DNA repair and that CCNA2-null progenitors thus experienced lengthened cell cycle. We demonstrate that CCNA2-null progenitors suffer abnormal DNA repair, and implicate Cyclin A2 in double-strand break repair. Cyclin A2's DNA repair functions are conserved among cell lines, neural progenitors, and hippocampal neurons. We further demonstrate that neuronal CCNA2 ablation results in learning and memory deficits in aged mice.

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Section: Discussionsupporting

confidence: 80%

Cyclin A2 promotes DNA repair in the brain during both development and aging

Gygli

Chang

Gokozan

et al. 2016

Aging

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“…BRCA1 was also found to be reduced in the brains of AD patients and human amyloid precursor protein (hAPP) transgenic mice (Suberbielle et al, 2015). Since HR is not the pathway of choice in post-mitotic cells these results are difficult to interpret.…”

Section: Dsb Processing and Repair As A Function Of Agementioning

confidence: 99%

Do DNA Double-Strand Breaks Drive Aging?

2016

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DNA double-strand breaks (DSBs) are rare but highly toxic lesions, requiring orchestrated and conserved machinery to prevent adverse consequences, such as cell death and cancer-causing genome structural mutations. DSBs trigger the DNA damage response (DDR) that directs a cell to repair the break, undergo apoptosis or become senescent. There is increasing evidence that the various endpoints of DSB processing by different cells and tissues are part of the aging phenotype, with each stage of the DDR associated with specific aging pathologies. In this perspective we discuss the possibility that DSBs are major drivers of intrinsic aging, highlighting the dynamics of spontaneous DSBs in relation to aging, the distinct age-related pathologies induced by DSBs, and the segmental progeroid phenotypes in humans and mice with genetic defects in DSB repair. A model is presented as to how DSBs could drive some of the basic mechanisms underlying age-related functional decline and death.

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“…In the brains of AD patients, BRCA1 levels are reduced, and likewise DNA repair capacity is reduced. BRCA1 was also found reduced in AD mouse brains and BRCA1 depletion caused learning and memory deficits (Suberbielle et al, 2015). Thus, these results indicate that DNA damage normally occurs during brain activity and that if we can improve double strand break repair capacity in AD brains, aspects of AD may be ameliorated.…”

Section: Dna Damage In Admentioning

confidence: 99%

Genome instability in Alzheimer disease

Song

Croteau

et al. 2017

Mechanisms of Ageing and Development

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. Autosomal dominant, familial AD (fAD) is very rare and caused by mutations in amyloid precursor protein (APP), presenilin-1 (PSEN-1), and presenilin-2 (PSEN-2) genes. The pathogenesis of sporadic AD (sAD) is more complex and variants of several genes are associated with an increased lifetime risk of AD. Nuclear and mitochondrial DNA integrity is pivotal during neuronal development, maintenance and function. DNA damage and alterations in cellular DNA repair capacity have been implicated in the aging process and in age-associated neurodegenerative diseases, including AD. These findings are supported by research using animal models of AD and in DNA repair deficient animal models. In recent years, novel mechanisms linking DNA damage to neuronal dysfunction have been identified and have led to the development of noninvasive treatment strategies. Further investigations into the molecular mechanisms connecting DNA damage to AD pathology may help to develop novel treatment strategies for this debilitating disease. Here we provide an overview of the role of genome instability and DNA repair deficiency in AD pathology and discuss research strategies that include genome instability as a component

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DNA repair factor BRCA1 depletion occurs in Alzheimer brains and impairs cognitive function in mice

Cited by 153 publications

References 70 publications

Cyclin A2 promotes DNA repair in the brain during both development and aging

Cyclin A2 promotes DNA repair in the brain during both development and aging

Do DNA Double-Strand Breaks Drive Aging?

Genome instability in Alzheimer disease

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