Author ORCID Identifier
Date of Graduation
5-2024
Document Type
Dissertation (PhD)
Program Affiliation
Neuroscience
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
David Grosshans, M.D.,Ph.D.
Committee Member
Michael Beierlein, Ph.D.
Committee Member
Joseph Duman, Ph.D.
Committee Member
Rodrigo Morales, Ph.D.
Committee Member
Gabriel Sawakuchi, Ph.D.
Abstract
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. This study shows that 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 response (DDR). Importantly, H2AX levels significantly decrease after irradiation in the absence of tau, elucidating tau's vital role in neuronal DDR. 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.
This study also 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 viii 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, this study provides 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.
Keywords
Radiation-induced injury, microtubule-associated tau, synaptic homeostasis, DNA damage repair response