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

IF 9.6 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Riya Thomas, Die Zhang, Christopher A. Cronkite, Rintu Thomas, Sanjay K. Singh, Lawrence F. Bronk, Rodrigo F. Morales, Joseph G. Duman, David R. Grosshans
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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.

Abstract Image

损伤中tau介导修复反应和突触稳态的亚细胞功能
终末分化细胞(如神经元)的损伤反应受到帮助维持体内平衡的途径的严格调节。在脑辐射中遭受神经元损伤的癌症患者,其认知能力下降与原发性神经退行性疾病相似。许多研究已经调查了辐射对大脑增殖细胞的影响,但对有丝分裂后分化神经元的影响,特别是结构和功能的改变,在很大程度上仍然是难以捉摸的。我们发现微管相关的tau蛋白通过修复中心和突触调节通路的区隔功能在神经元损伤反应中起关键作用。电离辐射诱导的损伤急性诱导细胞核中磷酸化tau蛋白的增加,在那里它直接与组蛋白2AX (H2AX)相互作用,这是一种DNA损伤修复(DDR)标记。tau的缺失显著降低了照射后H2AX的磷酸化,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蛋白的缺失增加了真核延伸因子水平,这是辐照后蛋白质翻译的积极调节因子。这种最初的反应级联到突触蛋白的显著增加,导致体内平衡被破坏。在下游,新的目标识别测试显示,辐照后,tau基因敲除小鼠的学习和记忆能力下降,脑电图活动包含增加的δ和θ波段振荡,这在痴呆患者中很常见。我们的研究结果证明了tau蛋白在急性损伤反应中的多功能作用,从细胞核中的DDR反应到神经元内的突触功能。这些知识对于开发针对高危人群和弱势人群认知衰退中的神经损伤的治疗策略至关重要。
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来源期刊
Molecular Psychiatry
Molecular Psychiatry 医学-精神病学
CiteScore
20.50
自引率
4.50%
发文量
459
审稿时长
4-8 weeks
期刊介绍: Molecular Psychiatry focuses on publishing research that aims to uncover the biological mechanisms behind psychiatric disorders and their treatment. The journal emphasizes studies that bridge pre-clinical and clinical research, covering cellular, molecular, integrative, clinical, imaging, and psychopharmacology levels.
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