Neuroimmune signaling mediates astrocytic nucleocytoplasmic disruptions and stress granule formation associated with TDP-43 pathology

Neuroimmune signaling mediates astrocytic nucleocytoplasmic disruptions and stress granule formation associated with TDP-43 pathology

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 intracellula...

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Main Authors: Constance Zhou, Evelyn J. Hardin, Till S. Zimmer, Stephanie Jackvony, Daniel Barnett, Noopur Khobrekar, Elisa Giacomelli, Lorenz Studer, Adam L. Orr, Anna G. Orr
Format: Article
Language:English
Published: Elsevier 2025-07-01
Series:Neurobiology of Disease
Subjects:
Neurodegeneration
TDP-43
Astrocytes
Nuclear pore
Neuroimmune signaling
Stress granules
Online Access:http://www.sciencedirect.com/science/article/pii/S096999612500155X
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Summary: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.
ISSN:1095-953X

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