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Updated: May 26, 2026
10:36
Modeling Neuronal Death and Degeneration in Mouse Primary Cerebellar Granule Neurons
Published on: November 6, 2017
DNA double-strand break signaling induces aberrant neuronal activity
Biorxiv : the Preprint Server for Biology
|May 25, 2026
Summary
Aberrant neuronal activity in neurodegenerative diseases is linked to DNA double-strand break (DSB) and p53 pathway activation. Inhibiting p53 offers a new therapeutic strategy for tauopathies.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Aberrant neuronal activity is an early hallmark of neurodegenerative disorders like tauopathy.
- The underlying mechanisms driving abnormal neuronal activity remain largely unknown.
- Understanding these mechanisms is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the link between DNA double-strand break (DSB) / p53 pathway activation and aberrant neuronal activity.
- To explore the therapeutic potential of p53 inhibition in neurodegenerative diseases.
Main Methods:
- Induction of DSBs or prevention of p53 degradation to activate the p53 pathway in mouse and human neurons.
- Analysis of p53-responsive gene expression in neurons.
- Utilizing human iPSC-based cerebral organoid models of frontotemporal dementia.
- Pharmacological inhibition of p53 transcriptional activity.
Main Results:
- p53 pathway activation, induced by DSBs or inhibited degradation, leads to aberrant neuronal activity.
- p53 activation upregulates genes involved in synaptic transmission.
- Elevated p53-responsive genes are found in Alzheimer's disease neurons with neurofibrillary tangles (NFTs).
- p53 inhibition in frontotemporal dementia organoids reduced aberrant neuronal calcium fluctuations.
Conclusions:
- A direct relationship exists between DSB/p53 pathway activation and aberrant neuronal activity.
- p53 inhibition presents a promising therapeutic avenue for neurodegenerative diseases associated with tauopathy.
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