Neuroimmune signaling mediates astrocytic nucleocytoplasmic disruptions and stress granule formation associated with TDP-43 pathology Journal Article
| Authors: | Zhou, C.; Hardin, E. J.; Zimmer, T. S.; Jackvony, S.; Barnett, D.; Khobrekar, N.; Giacomelli, E.; Studer, L.; Orr, A. L.; Orr, A. G. |
| Article Title: | Neuroimmune signaling mediates astrocytic nucleocytoplasmic disruptions and stress granule formation associated with TDP-43 pathology |
| Abstract: | Alterations in transactivating response region DNA-binding protein 43 (TDP-43) are prevalent in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurological disorders. TDP-43 influences neuronal functions and might also affect glial cells. However, specific intracellular effects of TDP-43 alterations on glial cells and underlying mechanisms are not clear. We report that TDP-43 dysregulation in mouse and human cortical astrocytes causes nucleoporin mislocalization, nuclear envelope remodeling, and changes in nucleocytoplasmic protein transport. These effects are dependent on interleukin-1 (IL-1) receptor activity and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and are associated with the formation of cytoplasmic stress granules. Stimulation of IL-1 receptors and NF-κB signaling are necessary and sufficient to induce astrocytic stress granules and rapid nucleocytoplasmic changes, which are broadly alleviated by inhibition of the integrated stress response. These findings establish that TDP-43 alterations and neuroimmune factors can induce nucleocytoplasmic changes through NF-κB signaling, revealing mechanistic convergence of proteinopathy and neuroimmune pathways onto glial nucleocytoplasmic disruptions that may occur in diverse neurological conditions. © 2025 The Author(s) |
| Keywords: | immunohistochemistry; signal transduction; controlled study; dna binding protein; genetics; dna-binding proteins; nonhuman; mouse; animal; metabolism; animals; mice; animal tissue; animal experiment; astrocyte; immunoglobulin enhancer binding protein; pathology; immunoreactivity; transcriptomics; mice, inbred c57bl; physiology; c57bl mouse; immunology; fluorescence in situ hybridization; genetic transfection; cell culture; immunocytochemistry; nf-kappa b; western blotting; immunomodulation; real time polymerase chain reaction; oxidative stress; rna extraction; astrocytes; neurodegeneration; oligodendroglia; nuclear pore; gene ontology; cell disruption; stress granules; induced pluripotent stem cell; physiological stress; humans; human; article; neuroimmunomodulation; immunofluorescence assay; tdp-43; tar dna binding protein; integrated stress response; tdp-43 proteinopathies; tdp 43 proteinopathy; tardbp protein, human; stress granule; neuroimmune signaling; tardbp protein, mouse; astrocytic nucleocytoplasmic disruption |
| Journal Title: | Neurobiology of Disease |
| Volume: | 211 |
| ISSN: | 09699961 |
| Publisher: | The Author(s) |
| Date Published: | 2025-07-01 |
| Start Page: | 106939 |
| Language: | English |
| DOI: | 10.1016/j.nbd.2025.106939 |
| PUBMED: | 40339618 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
