美国威尔康奈尔医学院Li Gan等研究人员合作发现，Tau交互组映射出与神经退行性相关的突触和线粒体过程。相关论文于2022年1月20日在线发表在《细胞》杂志上。
研究人员表示，Tau（MAPT）驱动阿尔茨海默病（AD）和其他Tau病理的神经元功能障碍。
为了剖析潜在的机制，研究人员将工程化的抗坏血酸过氧化物酶（APEX）方法与定量亲和纯化质谱法（AP-MS）相结合，然后用接近连接法（PLA）来描述了由神经元活动和导致人类诱导多能干细胞（iPSC）衍生的神经元中的额颞叶痴呆（FTD）突变所改变的Tau交互组。
研究人员建立了Tau在活动依赖性Tau分泌过程中与突触前囊泡蛋白的相互作用，并将Tau结合位点映射到整体突触囊泡蛋白的细胞膜域。结果表明，FTD突变损害了生物能量学，并明显减弱了Tau与线粒体蛋白的相互作用，这在多个队列的AD大脑中被下调，并与疾病严重程度相关。
这些具有精致空间分辨率的多模态和动态Tau交互组揭示了Tau在神经元功能和疾病中的作用，并突出了阻断Tau介导的发病机制的潜在治疗目标。
附：英文原文
Title: Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration
Author: Tara E. Tracy, Jesus Madero-Pérez, Danielle L. Swaney, Timothy S. Chang, Michelle Moritz, Csaba Konrad, Michael E. Ward, Erica Stevenson, Ruth Hüttenhain, Grant Kauwe, Maria Mercedes, Lauren Sweetland-Martin, Xu Chen, Sue-Ann Mok, Man Ying Wong, Maria Telpoukhovskaia, Sang-Won Min, Chao Wang, Peter Dongmin Sohn, Jordie Martin, Yungui Zhou, Wenjie Luo, John Q. Trojanowski, Virginia M.Y. Lee, Shiaoching Gong, Giovanni Manfredi, Giovanni Coppola, Nevan J. Krogan, Daniel H. Geschwind, Li Gan
Issue&Volume: 2022-01-20
Abstract: Tau (MAPT) drives neuronal dysfunction in Alzheimer disease (AD) and other tauopathies. To dissect the underlying mechanisms, we combined an engineered ascorbic acid peroxidase (APEX) approach with quantitative affinity purification mass spectrometry (AP-MS) followed by proximity ligation assay (PLA) to characterize Tau interactomes modified by neuronal activity and mutations that cause frontotemporal dementia (FTD) in human induced pluripotent stem cell (iPSC)-derived neurons. We established interactions of Tau with presynaptic vesicle proteins during activity-dependent Tau secretion and mapped the Tau-binding sites to the cytosolic domains of integral synaptic vesicle proteins. We showed that FTD mutations impair bioenergetics and markedly diminished Tau’s interaction with mitochondria proteins, which were downregulated in AD brains of multiple cohorts and correlated with disease severity. These multimodal and dynamic Tau interactomes with exquisite spatial resolution shed light on Tau’s role in neuronal function and disease and highlight potential therapeutic targets to block Tau-mediated pathogenesis.
DOI: 10.1016/j.cell.2021.12.041
Source: https://www.cell.com/cell/fulltext/S0092-8674(21)01563-4