DNA Double Strand Breaks in the Context of Tauopathy

The accumulation of altered tau protein, forming harmful aggregates, is a feature of a number of age-related neurodegenerative conditions, classed as tauopathies. This interesting paper discusses the evidence for tauopathies to be associated with an increased burden of double strand breaks, a form of DNA damage. Such damage is disruptive if prevalent, and recent evidence suggests that even repaired double strand breaks alter cell epigenetics in ways that encourage age-related declines in cell function. The researchers here suggest a bidirectional relationship, with tau pathology both degrading DNA repair mechanisms, and being driven by DNA damage.

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 (p-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.

In summary, neurons are physiologically exposed to various crises, such as aging, oxidative stress, genetic mutation, and excitotoxicity, all of which cause DNA damage. Under normal conditions, when DNA damage occurs, cytoskeletal proteins, such as microtubules, polymerize to execute DNA repair, and they might form a link with the nuclear membrane for the repair. Tau may well be involved in the rearrangement of microtubules to assist this process. However, the excessive DNA damage may cause accumulation of p-tau and may disassemble microtubules, which may exacerbate DNA damage and lead to neuronal cell death.

Link: https://doi.org/10.1038/s42003-022-03312-0


Can anyone suggest papers which look into the frequency of DSBs vs single letter mutations?

A DSB does not create DNA damage, correct? However, it creates epigenetic damage?

Posted by: Matt at May 3rd, 2022 6:15 AM

It's not great that the researcher that found that DSBs create epigenetic drift was David Sinclair's lab. He's been refuted on prior basic research.

Are there any other labs that duplicated this work on DSBs creating epigenetic drift?

Posted by: Matt at May 3rd, 2022 6:16 AM

This is a stealth NHEJ article. I wonder if science journals are actively suppressing discussion of NHEJ, so authors have to do this.

Posted by: Thomas Schaefer at May 5th, 2022 8:02 AM
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