DNA double-strand break signaling induces aberrant neuronal activity.

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 Alzheimer's 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.