Journal Article

Neurotoxic microglia promote TDP-43 proteinopathy in progranulin deficiency

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

2020

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 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