DNA double-strand break signaling induces aberrant neuronal activity

Pao, P.-C.; Liu, L.; Watson, L. A.; Lee, A.; Seguin, A.; Dong, D.; Rasheed, S.; Staab, C.; King, O.; Geigenmüller, U.; Penney, J.; Gao, F.; Muhtaseb, A.; Raju, R. M.; Tsai, L.-H.

doi:10.64898/2026.05.11.724110

bioRxiv · 10.64898/2026.05.11.724110

DNA double-strand break signaling induces aberrant neuronal activity

Pao, P.-C.·Liu, L.·Watson, L. A.·Lee, A.·Seguin, A.·Dong, D.·Rasheed, S.·Staab, C.·King, O.·Geigenmüller, U.·Penney, J.·Gao, F.·Muhtaseb, A.·Raju, R. M.·Tsai, L.-H.

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Abstract

Aberrant neuronal activity is an early pathological feature of numerous neurodegenerative disorders, including tauopathy, and is thought to play a role in disease progression. However, the mechanism underlying abnormal neuronal activity remains elusive. Here, we reveal a relationship between DNA double-strand break (DSB)/p53 pathway activation and aberrant neuronal activity. Activating p53 as part of the DNA damage response via DSB induction, or by preventing MDM2-mediated p53 degradation, causes aberrant activity in both mouse and human neurons. p53 activation induces the expression of genes regulating synaptic transmission, and p53-responsive gene upregulation is overrepresented in postmortem human Alzheimers disease neurons burdened with neurofibrillary tangles (NFTs). Using a human iPSC-based cerebral organoid model of frontotemporal dementia that exhibits relevant pathologies including elevated DSBs, aberrant neuronal activity, and NFTs, we show that inhibiting p53 transcriptional activity with a small molecule ameliorates aberrant calcium fluctuations in neurons. Together, our findings highlight p53 inhibition as a novel therapeutic strategy to counter aberrant neuronal activity in neurodegenerative diseases characterized by tauopathy.

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Pao, P.-C., Liu, L., Watson, L. A., Lee, A., Seguin, A., Dong, D., Rasheed, S., Staab, C., King, O., Geigenmüller, U., Penney, J., Gao, F., Muhtaseb, A., Raju, R. M., Tsai, L.-H.. 2026-05-13. DNA double-strand break signaling induces aberrant neuronal activity. https://doi.org/10.64898/2026.05.11.724110

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