Grosshans David, Thomas Riya, Zhang Die, Cronkite Christopher, Thomas Rintu, Singh Sanjay, Bronk Lawrence, Morales Rodrigo, Duman Joseph
MD Anderson Cancer Center.
The University of Texas Health Science Center at Houston.
Res Sq. 2024 Feb 29:rs.3.rs-3897741. doi: 10.21203/rs.3.rs-3897741/v1.
Injury responses in terminally differentiated cells such as neurons is 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 increase in phosphorylated tau in the nucleus and directly interacts with histone 2AX (H2AX), a DNA damage repair (DDR) marker. Loss of tau significantly reduced H2AX after irradiation, indicating that tau may play an important role in neuronal DDR response. We also observed that loss of tau increases eukaryotic elongation factor levels after irradiation, the latter being a positive regulator of protein translation. This cascades into a significant increase in synaptic proteins, resulting in disrupted homeostasis. Consequently, novel object recognition test showed decrease in learning and memory in tau-knockout mice after irradiation, and electroencephalographic activity showed increase in 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 a neuron. Such knowledge is vital to develop therapeutic strategies targeting neuronal injury in cognitive decline for at risk and vulnerable populations.
终末分化细胞（如神经元）中的损伤反应受到有助于稳态维持的信号通路的严格调控。接受脑部放射治疗且发生神经元损伤的癌症患者会出现与原发性神经退行性疾病类似的认知衰退。许多研究调查了辐射对大脑增殖细胞的影响，但辐射对已分化的、有丝分裂后的神经元的影响，尤其是其结构和功能改变，在很大程度上仍不清楚。我们发现，微管相关蛋白tau通过在以修复为中心的和突触调节通路中的区室化功能，在神经元损伤反应中起着关键作用。电离辐射诱导的损伤会急性诱导细胞核中磷酸化tau增加，并直接与DNA损伤修复（DDR）标志物组蛋白2AX（H2AX）相互作用。tau缺失显著降低了辐射后H2AX的水平，表明tau可能在神经元DDR反应中发挥重要作用。我们还观察到，tau缺失会增加辐射后真核生物延伸因子的水平，后者是蛋白质翻译的正调节因子。这进而导致突触蛋白显著增加，从而破坏了稳态。因此，新物体识别测试显示，辐射后tau基因敲除小鼠的学习和记忆能力下降，脑电图活动显示δ波和θ波振荡增加，这在痴呆症患者中很常见。我们的研究结果表明，tau在对损伤的急性反应中具有以前未明确的多功能作用，范围从细胞核中的DDR反应到神经元内的突触功能。这些知识对于为高危和脆弱人群制定针对认知衰退中神经元损伤的治疗策略至关重要。
