Neurotoxic microglia promote TDP-43 proteinopathy in progranulin deficiency

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 progranulin 1 , 2 . However, the mechanism leading to TDP-43 proteinopathy remains unclear. Here we use single-nucleus RNA sequencing...

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Published in	Nature (London) Vol. 588; no. 7838; pp. 459 - 465
Main Authors	Zhang, Jiasheng, Velmeshev, Dmitry, Hashimoto, Kei, Huang, Yu-Hsin, Hofmann, Jeffrey W., Shi, Xiaoyu, Chen, Jiapei, Leidal, Andrew M., Dishart, Julian G., Cahill, Michelle K., Kelley, Kevin W., Liddelow, Shane A., Seeley, William W., Miller, Bruce L., Walther, Tobias C., Farese, Robert V., Taylor, J. Paul, Ullian, Erik M., Huang, Bo, Debnath, Jayanta, Wittmann, Torsten, Kriegstein, Arnold R., Huang, Eric J.
Format	Journal Article
Language	English
Published	London Nature Publishing Group UK 17.12.2020 Nature Publishing Group
Subjects	13 13/51 14/19 14/63 38 38/39 38/91 631/378/1689/364 631/378/2596/1953 64 64/60 Age Aging - genetics Aging - pathology Alzheimer's disease Amyotrophic lateral sclerosis Animals Annotations Binding proteins Causes of Cell adhesion & migration Cell migration Cell Nucleus - genetics Cell Nucleus - pathology Coagulation Complement Activation - drug effects Complement Activation - immunology Complement C1q - antagonists & inhibitors Complement C1q - immunology Complement C3b - antagonists & inhibitors Complement C3b - immunology Culture Media, Conditioned - chemistry Culture Media, Conditioned - pharmacology CX3CR1 protein Cysteine proteinase Dendritic structure Diagnosis Disease Models, Animal DNA-Binding Proteins - metabolism Exocytosis Female Gene expression Genes Glycoproteins Health aspects Homeostasis Humanities and Social Sciences Kinases Localization Male MAP kinase Membrane proteins Membranes Mice Microglia Microglia - metabolism Microglia - pathology multidisciplinary Neurodegeneration Neurons Neurons - metabolism Neurons - pathology Neurotoxicity Neurotoxicity syndromes Normalizing Nuclear Pore - metabolism Nuclear Pore - pathology Phagocytosis Physiological aspects Progranulins - deficiency Progranulins - genetics Protease inhibitors Protein deficiency Protein kinase C Protein transport Protein-tyrosine kinase receptors Proteinase inhibitors Proteins Ras protein RNA-Seq Science Science (multidisciplinary) Signal transduction Single-Cell Analysis TDP-43 Proteinopathies - drug therapy TDP-43 Proteinopathies - genetics TDP-43 Proteinopathies - metabolism TDP-43 Proteinopathies - pathology Thalamus Thalamus - metabolism Thalamus - pathology Transcriptome Tyrosine United States
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ISSN	0028-0836 1476-4687 1476-4687
DOI	10.1038/s41586-020-2709-7

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Summary:	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 progranulin 1 , 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. In the absence of progranulin, microglia enter a disease-specific state that causes endolysosomal dysfunction and neurodegeneration, and these microglia promote TDP-43 granule formation, nuclear pore defects and cell death specifically in excitatory neurons via the complement activation pathway.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Literature Review-3 content type line 23 These authors contributed equally to this work J.Z., D.V., K.H., Y.H., A.R.K. and E.J.H. conceived the project, designed the experiments, and wrote the paper. D.V., J.Z. and K.H. performed single-cell transcriptomics and related work, D.V. performed bioinformatics analyses, K.H. performed NanoString nCounter work, J.Z., K.H., Y.H.,, J.W.H., M.K.C., A.M.L. and J.G.D. performed in vitro cultures, immunohistochemistry and quantifications for cell death, TDP-43 granules and nuclear pore defects, J.Z. performed stereology-based quantifications, A.M.L., E.M.U. and J.D. provided expertise related to stress granule and endolysosomal phenotypes, K.W.K., W.W.S., B.L.M., T.C.W. and R.V.F. contributed expertise, reagents and analyses related Grn mouse models, X.S., J.W.H., J.C. and B.H. provided assistance with 3D Structured Illumination Microscopy, J.P.T. and T.W. provided reagents and assisted with mCherry-TDP-43 live imaging, and S.A.L. provided expertise in glial gene expression. All authors reviewed and edited the manuscript. Author Contributions
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-020-2709-7