Neuroimmune signaling mediates astrocytic nucleocytoplasmic disruptions and stress granule formation associated with TDP-43 pathology.
| Publication Type | Academic Article |
| Authors | Zhou C, Hardin E, Zimmer T, Jackvony S, Barnett D, Khobrekar N, Giacomelli E, Studer L, Orr A, Orr A |
| Journal | Neurobiol Dis |
| Volume | 211 |
| Pagination | 106939 |
| Date Published | 05/09/2025 |
| ISSN | 1095-953X |
| Keywords | Astrocytes, DNA-Binding Proteins, Signal Transduction, Stress Granules, Neuroimmunomodulation, TDP-43 Proteinopathies |
| 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. |
| DOI | 10.1016/j.nbd.2025.106939 |
| PubMed ID | 40339618 |
| PubMed Central ID | PMC12240875 |