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Subcellular functions of tau mediate repair response and synaptic homeostasis in injury

Molecular Psychiatry (2025)Cite this article

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Abstract

Injury responses in terminally differentiated cells such as neurons are tightly regulated by pathways aiding homeostatic maintenance. Cancer patients subjected to neuronal injury in brain radiation experience cognitive declines similar to those seen in primary neurodegenerative diseases. Numerous studies have investigated the effect of radiation in proliferating cells of the brain, yet the impact in differentiated, post-mitotic neurons, especially the structural and functional alterations remain largely elusive. We identified that microtubule-associated tau is a critical player in neuronal injury response via compartmentalized functions in both repair-centric and synaptic regulatory pathways. Ionizing radiation-induced injury acutely induces an increase in phosphorylated tau in the nucleus where it directly interacts with histone 2AX (H2AX), a DNA damage repair (DDR) marker. Loss of tau significantly reduced H2AX phosphorylation after irradiation, indicating that tau may play an important role in the neuronal DDR response. We also observed that loss of tau increases eukaryotic elongation factor levels, a positive regulator of protein translation after irradiation. This initial response cascades into a significant increase in synaptic proteins, resulting in disrupted homeostasis. Downstream, the novel object recognition test showed a decrease in learning and memory in tau-knockout mice after irradiation, and electroencephalographic activity contained increased delta and theta band oscillations, often seen in dementia patients. Our findings demonstrate tau’s previously undefined, multifunctional role in acute responses to injury, ranging from DDR response in the nucleus to synaptic function within neurons. Such knowledge is vital to develop therapeutic strategies targeting neuronal injury in cognitive decline for at risk and vulnerable populations.

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Fig. 1: Neuronal injury induces nuclear sequestration of phosphorylated tau in primary cortical neurons.
Fig. 2: IP-MS and ChIP-Seq identifies unique ptau-interactors and ptau-chromatin sites following radiation-induced neuronal injury.
Fig. 3: DNA damage repair is diminished in brains of tau-knockout mice.
Fig. 4: Translation machinery and protein synthesis is modulated in tau-knockdown hiPSC-derived cerebral organoids and tau-knockout mice after injury.
Fig. 5: Synaptic composition is altered in response to injury and tau status.
Fig. 6: Radiation injury and tau knockout worsens cognitive functioning and impairs spontaneous firing patterns and spectral power in tau knockout mice.

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All relevant data are included in the paper. Data are available from the corresponding author upon reasonable request.

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Acknowledgements

We are grateful to University of Texas Medical Branch, especially Dr. Aaron Bailey for the IP-MS assay and preliminary analysis, and ActiveMotif for the ChIP-Seq assay and analysis. This study was supported by funding from the National Institute of Health (R01CA256848, R01CA208535, R01CA255596, and R01CA219667). Figure illustrations were generated on BioRender.

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Authors and Affiliations

  1. MD Anderson-UT Health Houston Graduate School of Biomedical Sciences, Houston, TX, USA

    Riya Thomas

  2. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Die Zhang & David R. Grosshans

  3. Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA

    Christopher A. Cronkite

  4. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    Rintu Thomas

  5. Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Sanjay K. Singh

  6. Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Lawrence F. Bronk

  7. Department of Neurology, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Rodrigo F. Morales

  8. Centro Integrativo de Biologia y Quimica Aplicada (CIBQA). Universidad Bernardo O’Higgins, Santiago, Chile

    Rodrigo F. Morales

  9. Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA

    Joseph G. Duman

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Contributions

Conceptualization, Riya T and DRG; Methodology, Riya T; Investigation, Riya T, DZ, CAC, Rintu T, SKS, LFB; Writing – Original Draft, Riya T; Writing – Review & Editing, Riya T, DZ, CAC, Rintu T, SKS, LFB, RFM, JGD, DRG; Funding Acquisition, DRG; Resources, DRG; Supervision, DRG.

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Correspondence to David R. Grosshans.

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Thomas, R., Zhang, D., Cronkite, C.A. et al. Subcellular functions of tau mediate repair response and synaptic homeostasis in injury. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03029-6

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