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神经毒性小胶质细胞促进前颗粒蛋白缺乏的TDP-43蛋白病
2020-09-02 16:31

美国加州大学旧金山分校Eric J. Huang研究小组发现,神经毒性小胶质细胞促进前颗粒蛋白缺乏的TDP-43蛋白病。相关论文于2020年8月31日在线发表于《自然》。

研究人员使用单核RNA测序(snRNA-seq)发现,前颗粒蛋白缺乏会促进小胶质细胞从稳态到疾病特异性状态的转变,从而引起溶酶体功能障碍和神经变性。即使在离体培养Grn-/-小胶质细胞时,这些缺陷仍然存在。此外,snRNA-seq揭示了疾病末期兴奋性神经元的选择性丢失,其特征是突出的核和细胞质TDP-43颗粒以及核孔缺陷。

值得注意的是,来自Grn-/-小胶质细胞的条件培养基足以通过补体激活途径促进兴奋性神经元中TDP-43颗粒的形成、核孔缺陷和细胞死亡。与这些结果一致,敲除C1qa和C3可减轻小胶质细胞毒性,并挽救TDP-43蛋白病和神经变性。这些结果揭示了神经变性期间慢性小胶质细胞毒性对TDP-43蛋白病的新贡献。

据悉,RNA结合蛋白TDP-43在神经元中的异常聚集是额颞叶变性(由前颗粒蛋白单倍计量不足引起)的标志。然而,导致TDP-43蛋白病的机制仍不清楚。

附:英文原文

Title: Neurotoxic microglia promote TDP-43 proteinopathy in progranulin deficiency

Author: Jiasheng Zhang, Dmitry Velmeshev, Kei Hashimoto, Yu-Hsin Huang, Jeffrey W. Hofmann, Xiaoyu Shi, Jiapei Chen, Andrew M. Leidal, Julian G. Dishart, Michelle K. Cahill, Kevin W. Kelley, Shane A. Liddelow, William W. Seeley, Bruce L. Miller, Tobias C. Walther, Robert V. Farese, J. Paul Taylor, Erik M. Ullian, Bo Huang, Jayanta Debnath, Torsten Wittmann, Arnold R. Kriegstein, Eric J. Huang

Issue&Volume: 2020-08-31

Abstract: Aberrant aggregation of RNA binding protein TDP-43 in neurons is a hallmark of frontotemporal lobar degeneration caused by progranulin haploinsufficiency1,2. However, the mechanism leading to TDP-43 proteinopathy remains unclear. Here we use single-nucleus RNA-sequencing (snRNA-seq) to show that progranulin deficiency promotes microglial transition from a homeostatic to disease-specific state that causes endolysosomal dysfunction and neurodegeneration. These defects persist even when Grn/ microglia are cultured ex vivo. In addition, snRNA-seq reveals selective loss of excitatory neurons at disease end-stage, characterized by prominent nuclear and cytoplasmic TDP-43 granules and nuclear pore defects. Remarkably, conditioned media from Grn/ microglia is sufficient to promote TDP-43 granule formation, nuclear pore defects and cell death in excitatory neurons via the complement activation pathway. Consistent with these results, deleting C1qa and C3 mitigates microglial toxicity, and rescues TDP-43 proteinopathy and neurodegeneration. These results uncover previously unappreciated contributions of chronic microglial toxicity to TDP-43 proteinopathy during neurodegeneration.

DOI: 10.1038/s41586-020-2709-7

Source: https://www.nature.com/articles/s41586-020-2709-7

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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