Neurotoxic microglia promote TDP-43 proteinopathy in progranulin deficiency

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 and Eric J. Huang ()
Additional contact information
Jiasheng Zhang: University of California San Francisco
Dmitry Velmeshev: University of California San Francisco
Kei Hashimoto: University of California San Francisco
Yu-Hsin Huang: University of California San Francisco
Jeffrey W. Hofmann: University of California San Francisco
Xiaoyu Shi: University of California San Francisco
Jiapei Chen: University of California San Francisco
Andrew M. Leidal: University of California San Francisco
Julian G. Dishart: University of California San Francisco
Michelle K. Cahill: University of California San Francisco
Kevin W. Kelley: University of California San Francisco
Shane A. Liddelow: NYU Langone Medical Center
William W. Seeley: University of California San Francisco
Bruce L. Miller: University of California San Francisco
Tobias C. Walther: T.H. Chan School of Public Health, Harvard University
Robert V. Farese: T.H. Chan School of Public Health, Harvard University
J. Paul Taylor: St Jude Children’s Hospital & Howard Hughes Medical Institute
Erik M. Ullian: University of California San Francisco
Bo Huang: University of California San Francisco
Jayanta Debnath: University of California San Francisco
Torsten Wittmann: University of California San Francisco
Arnold R. Kriegstein: University of California San Francisco
Eric J. Huang: University of California San Francisco

Nature, 2020, vol. 588, issue 7838, 459-465

Abstract: Abstract Aberrant aggregation of the RNA-binding protein TDP-43 in neurons is a hallmark of frontotemporal lobar degeneration caused by haploinsufficiency in the gene encoding progranulin1,2. However, the mechanism leading to TDP-43 proteinopathy remains unclear. Here we use single-nucleus RNA sequencing to show that progranulin deficiency promotes microglial transition from a homeostatic to a disease-specific state that causes endolysosomal dysfunction and neurodegeneration in mice. These defects persist even when Grn−/− microglia are cultured ex vivo. In addition, single-nucleus RNA sequencing reveals selective loss of excitatory neurons at disease end-stage, which is characterized by prominent nuclear and cytoplasmic TDP-43 granules and nuclear pore defects. Remarkably, conditioned media from Grn−/− microglia are 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, deletion of the genes encoding 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.

Date: 2020
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DOI: 10.1038/s41586-020-2709-7

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