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神经突触的形成和修剪的严格调控，对于发育和成熟大脑中的神经回路的功能发挥非常重要。众多研究表明异常的突触功能和修剪是神经精神疾病和神经退行性疾病（如精神分裂症和阿尔茨海默病）的关键致病机理【1-3】。先天免疫分子，包括经典补体通路，在大脑发育过程中的神经环路精细化以及病理情况下的突触修剪中发挥着重要作用【4-6】。经典补体通路的启动因子C1q与突触结合，通过下游级联反应激活后，从而引起小胶质细胞吞噬补体调控的突触【4, 7, 8】。该过程在多种中枢神经系统疾病中异常激活（包括阿尔茨海默病、病毒引起的突触丢失、额颞叶痴呆、亨廷顿病以及精神分裂症）导致突触丢失并引起的认知功能下降【6-12】。尽管C1q 在神经退行性疾病和突触修饰中发挥着重要作用，但是对于如何调控大脑中C1q以及下游补体通路的活性尚不清楚。2023年3月29日，来自约翰霍普金斯医学院神经科学系的Paul Worley研究团队以及来自broad Institute of MIT 的Morgan sheng研究团队合作在Science Translational Medicine以封面文章发表了题为：The neuronal pentraxin Nptx2 regulates complement activity and restrains microglia-mediated synapse loss in neurodegeneration的研究文章。该研究首次发现在成熟大脑中Nptx2通过调节补体通路活性来调控小胶质细胞所介导的突触修饰，同时还发现在FTD患者的Nptx2下降可能会加重补体通路所介导的神经退行性疾病。研究团队首先通过多种生化和细胞实验技术证实了五聚体蛋白Nptx2能够直接和C1q相互作用并调控其活性。紧接着在Nptx2敲除的小鼠中发现补体活性的增强，以及C1q依赖的小胶质细胞突触吞噬增多和兴奋性突触的丧失。为了进一步研究Nptx2通过调控C1q所介导的小胶质细胞的突触修饰在疾病模型的作用。作者使用体外神经炎症培养模型以及TauP301S小鼠，通过AAV在神经细胞中过表达Nptx2抑制补体通路活性，并改善小胶质细胞介导的突触丢失。最后作者通过对FTD患者的脑脊液研究分析显示，有明显症状的FTD患者的Nptx2和Nptx2-C1q蛋白复合物浓度降低，同时C1q的显著升高和激活的C3水平呈正相关。这项工作揭示了在成熟大脑中，神经细胞五聚体蛋白Nptx2是补体蛋白C1q的活性调节因子。缺失Nptx2的小鼠大脑表现出补体活性增强以及突触丢失表型。相比之下，在神经退行性小鼠模型TauP301S中通过基因载体AAV过表达Nptx2可降低补体活性以及突触丢失。综合这些发现以及对FTD患者脑脊液样本中Nptx2、C1q、C3b和 C1q-Nptx2 复合物的丰度分析表明，Nptx2可能是与补体通路相关的神经退行性疾病的治疗靶点。约翰霍普金斯大学医学院神经科学系Paul Worley实验室诚聘postdoc. 欢迎有意者投递简历。https://jinshuju.net/f/ZqXwZt或扫描二维码投递简历原文链接：
http://doi.org/10.1126/scitranslmed.adf0141
制版人：十一
1. L. Volk, S.-L. Chiu, K. Sharma, R. L. Huganir, Glutamate Synapses in Human Cognitive Disorders. Annu Rev Neurosci. 38, 1–23 (2014).2. D. K. Wilton, L. Dissing-Olesen, B. Stevens, Neuron-Glia Signaling in Synapse Elimination. Annu Rev Neurosci. 42, 107–127 (2019).3. U. Neniskyte, C. T. Gross, Errant gardeners: glial-cell-dependent synaptic pruning and neurodevelopmental disorders. Nat Rev Neurosci. 18, 658–670 (2017).4. B. Stevens, N. J. Allen, L. E. Vazquez, G. R. Howell, K. S. Christopherson, N. Nouri, K. D. Micheva, A. K. Mehalow, A. D. Huberman, B. Stafford, A. Sher, A. M. Litke, J. D. Lambris, S. J. Smith, S. W. M. John, B. A. Barres, The Classical Complement Cascade Mediates CNS Synapse Elimination. Cell. 131, 1164–1178 (2007).5. D. P. Schafer, E. K. Lehrman, A. G. Kautzman, R. Koyama, A. R. Mardinly, R. Yamasaki, R. M. Ransohoff, M. E. Greenberg, B. A. Barres, B. Stevens, Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner. Neuron. 74, 691–705 (2012).6. C. J. Bohlen, B. A. Friedman, B. Dejanovic, M. Sheng, Microglia in Brain Development, Homeostasis, and Neurodegeneration. Annu Rev Genet. 53, 1–26 (2019).7. B. Dejanovic, M. A. Huntley, A. D. Mazière, W. J. Meilandt, T. Wu, K. Srinivasan, Z. Jiang, V. Gandham, B. A. Friedman, H. Ngu, O. Foreman, R. A. D. Carano, B. Chih, J. Klumperman, C. Bakalarski, J. E. Hanson, M. Sheng, Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies. Neuron. 100, 1322-1336.e7 (2018).8. B. Dejanovic, T. Wu, M.-C. Tsai, D. Graykowski, V. D. Gandham, C. M. Rose, C. E. Bakalarski, H. Ngu, Y. Wang, S. Pandey, M. G. Rezzonico, B. A. Friedman, R. Edmonds, A. D. Mazière, R. Rakosi-Schmidt, T. Singh, J. Klumperman, O. Foreman, M. C. Chang, L. Xie, M. Sheng, J. E. Hanson, Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer’s disease mouse models. Nat Aging. 2, 837–850 (2022).9. T. Wu, B. Dejanovic, V. D. Gandham, A. Gogineni, R. Edmonds, S. Schauer, K. Srinivasan, M. A. Huntley, Y. Wang, T.-M. Wang, M. Hedehus, K. H. Barck, M. Stark, H. Ngu, O. Foreman, W. J. Meilandt, J. Elstrott, M. C. Chang, D. V. Hansen, R. A. D. Carano, M. Sheng, J. E. Hanson, Complement C3 Is Activated in Human AD Brain and Is Required for Neurodegeneration in Mouse Models of Amyloidosis and Tauopathy. Cell Reports. 28, 2111-2123.e6 (2019).10. A. L. Comer, T. Jinadasa, B. Sriram, R. A. Phadke, L. N. Kretsge, T. P. H. Nguyen, G. Antognetti, J. P. Gilbert, J. Lee, E. R. Newmark, F. S. Hausmann, S. Rosenthal, K. L. Kot, Y. Liu, W. W. Yen, B. Dejanovic, A. Cruz-Martín, Increased expression of schizophrenia-associated gene C4 leads to hypoconnectivity of prefrontal cortex and reduced social interaction. Plos Biol. 18, e3000604 (2020).11. S. Hong, V. F. Beja-Glasser, B. M. Nfonoyim, A. Frouin, S. Li, S. Ramakrishnan, K. M. Merry, Q. Shi, A. Rosenthal, B. A. Barres, C. A. Lemere, D. J. Selkoe, B. Stevens, Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 352, aad8373 (2016).12. M. J. Vasek, C. Garber, D. Dorsey, D. M. Durrant, B. Bollman, A. Soung, J. Yu, C. Perez-Torres, A. Frouin, D. K. Wilton, K. Funk, B. K. DeMasters, X. Jiang, J. R. Bowen, S. Mennerick, J. K. Robinson, J. R. Garbow, K. L. Tyler, M. S. Suthar, R. E. Schmidt, B. Stevens, R. S. Klein, A complement–microglial axis drives synapse loss during virus-induced memory impairment. Nature. 534, 538–543 (2016).![]()
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