Nde1 is Required for Heterochromatin Compaction and Stability in Neocortical Neurons

Chomiak, Alison A.; Lowe, Clara C.; Guo, Yan; Pan, Hongna; McDaniel, Dennis P.; Zhou, Xiaoming; Zhou, Qiong; Doughty, Martin L.; Feng, Yuanyi

doi:10.2139/ssrn.3937607

Cited by 1 publication

(2 citation statements)

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“…The main fate of cells with Brap LOF is cellular senescence, driven primarily by recurrent DSBs due to insufficient silencing of satellite repeats 11,13 . The senescence state permits a direct communication of neurons with their supporting cells.…”

Section: Discussionmentioning

confidence: 99%

“…By studying chromatin remodeling in neurogenesis, we have recently shown that DSBs in neocortical neurons may arise from compromised epigenetic silencing of pericentric satellite DNA in mice with genetic deficiencies of Nde1 (neurodevelopment protein 1) and its interacting Brap (BRCA1-associated protein) 11 . The long tandem repeats of satellite DNA are intrinsically unstable and refractory to repair 12 .…”

Section: Introductionmentioning

confidence: 99%

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Senescence of cortical neurons following persistent DNA double-strand breaks induces cerebrovascular lesions

Feng

Kopsidas

Lowe

et al. 2023

Preprint

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DNA double strand breaks (DSBs), neuroinflammation, and vascular alterations in the brain are all associated with neurodegenerative disorders. However, it remains unclear how these neuropathological changes relate to each other and act synergistically to promote neurodegeneration. Here we reveal cerebrovascular defects caused by abrogating the BRCA1-assocaited protein Brap in cerebral cortical neurons in mice. Brap loss of function results in persistent DSBs and a senescence state in cortical neurons. In this state, upregulation of genes involving in cell secretion as well as encoding inflammatory and vasoactive factors leads to both ischemic and hemorrhagic damages to cerebral blood vessels. The vascular lesions intertwine with neuroinflammation and neuronal DSBs. They impair glycolytic metabolism, increase oxidative stress, and exacerbate neuronal DSBs, resulting in downregulation of genes essential for neuronal function. By demonstrating the non-cell-autonomous cerebrovascular impact of damaged neurons, our data suggest that DSBs can initiate brain-wide neurodegeneration through senescence-mediated secretion.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%