Novel Roles of Microtubule-Associated Tau in Radiation-Induced Brain Injury

Advisor: David Grosshans, MD, PhD

Injury responses in cells lacking proliferation capacity such as terminally differentiated neurons consists of complex mechanisms to ensure cellular homeostasis. Brain tumor patients undergoing radiation therapy experience cognitive impairments similar to those seen in patients suffering from neurodegenerative diseases. Despite the plethora of research into radiation effects on proliferating brain cells, the impact of radiation on differentiated, post-mitotic neurons, including their structural and functional alterations, remain largely elusive. However, microtubule-associated tau, an important partner of cytoskeletal structural stability emerges as a pivotal player in the radiation-induced neuronal injury response, demonstrating compartmentalized functions such as repair-centric mechanisms and synaptic homeostasis in part I of this study. Radiation-induced injury triggers an increase of phosphorylated tau in the nucleus, which directly interacts with histone 2AX (H2AX), a crucial marker of DNA damage repair (DDR). Importantly, H2AX levels significantly decrease after irradiation in the absence of tau, elucidating tau's vital role in neuronal DDR response. Loss of tau also results in an increase of eukaryotic elongation factor (a positive regulator of protein translation) levels after irradiation, further triggering a cascade of events resulting in disrupted synaptic protein homeostasis, alterations in neuronal oscillations, and distinct cognitive deficits.

Part II of this study highlights a post-translational modification of tau in radiation-induced injury. Immunoprecipitation-mass spectrometry analysis of human induced pluripotent stem cell (hiPSC)-derived neurons subjected to radiation-induced injury revealed unique methionine oxidation sites within fetal tau peptide sequences. Curiously, the absence of insoluble tau in irradiated hiPSC-derived neurons hints at potential alterations in tau aggregation propensity due to methionine oxidation, thereby modulating protein folding and function. Methionine oxidation is critical for protein activity, particularly under stressors such as radiation therapy. Given methionine's ubiquitous presence in all proteins, including microtubule-associated tau isoforms, investigating its oxidation dynamics in fetal tau amid radiation-induced stress is imperative. Moreover, the discovery of a truncated tau fragment in the cortex and hippocampus of young mice exposed to radiation underscores the cross-species relevance of these results. Collectively, these novel findings reveal a previously unexplored, post-translational modification landscape of fetal tau isoform in response to radiation-induced injury. This offers novel insights into tau protein dynamics with implications for neurodegenerative disease pathology and the management of cognitive decline in cancer patients undergoing radiation therapy.

In summation, Parts I and II provide insights into the novel roles of microtubule-associated tau in radiation-induced injury, which can potentially inform the development of therapeutic strategies with enhanced efficacy and specificity for at-risk and vulnerable populations.

Advisory Committee:
David Grosshans, MD, PhD, Chair
Michael Beierlein, PhD
Joseph Duman, PhD
Rodrigo Morales, PhD
Gabriel Sawakuchi, PhD

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