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

Topic: Brain proteins, microglia and lab models

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.

@article{zhou2025-40339618,
  author  = {Zhou, Constance Q. and Hardin, Evelyn J. and Zimmer, Till S. and Jackvony, Stephanie and BARNETT, DANIEL H. and Khobrekar, Noopur V. and Giacomelli, Elisa and Studer, Lorenz and others},
  title   = {{Neuroimmune signaling mediates astrocytic nucleocytoplasmic disruptions and stress granule formation associated with TDP-43 pathology}},
  journal = {Neurobiology of Disease},
  year    = {2025},
  doi     = {10.1016/j.nbd.2025.106939},
  pmid    = {40339618},
  url     = {https://doi.org/10.1016/j.nbd.2025.106939}
}

Key findings

• 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.
• 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.

Why it matters

In mouse and human cortical astrocytes, TDP-43 dysregulation caused nucleoporin mislocalization, nuclear envelope changes, and altered nucleocytoplasmic protein transport, effects that depended on IL-1 receptor activity and NF-κB signaling and were linked to stress granule formation. Inhibiting the integrated stress response broadly reduced these changes, pointing to a convergence of proteinopathy and neuroimmune pathways in glial cells.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1016/j.nbd.2025.106939
• PubMed: 40339618
• Original source →
• Free full text: Neurobiology of Disease →

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Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 20.

• Neurotoxic reactive astrocytes are induced by activated microglia Nature · 2017-01-01 · usefulness score 68/100 · Inflammation and the immune system
• TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD Nature neuroscience · 2018-01-08 · usefulness score 61/100 · Lewy body dementia
• Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis Neuron · 2013-08-01 · usefulness score 58/100 · Lewy body dementia
• TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia The Lancet. Neurology · 2010-10-01 · usefulness score 57/100 · Lewy body dementia
• The C9orf72 repeat expansion disrupts nucleocytoplasmic transport Nature · 2015-08-26 · usefulness score 57/100 · Lewy body dementia
• Functional roles of reactive astrocytes in neuroinflammation and neurodegeneration Nature reviews. Neurology · 2023-06-12 · usefulness score 56/100 · Inflammation and the immune system
• Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue PloS one · 2010-10-11 · usefulness score 55/100 · Lewy body dementia
• Stress Granule Assembly Disrupts Nucleocytoplasmic Transport Cell · 2018-04-05 · usefulness score 55/100 · Lewy body dementia
• Stress granules and neurodegeneration Nature reviews. Neuroscience · 2019-10-03 · usefulness score 55/100 · Lewy body dementia
• C9orf72 Dipeptide Repeats Impair the Assembly, Dynamics, and Function of Membrane-Less Organelles Cell · 2016-10-01 · usefulness score 54/100 · Lewy body dementia
• TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity The Journal of biological chemistry · 2009-05-22 · usefulness score 53/100 · Lewy body dementia
• ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43 Proceedings of the National Academy of Sciences of the United States of America · 2013-02-04 · usefulness score 53/100 · Lewy body dementia

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• Soluble P-tau217 reflects amyloid and tau pathology and mediates the association of amyloid with tau EMBO molecular medicine · 2021-05-05 · usefulness score 61/100
• Defining the Intestinal eCBome and Oxylipin Signaling Systems in a TDP‐43 Mouse Model of Frontotemporal Dementia The FASEB Journal · 2026-01-12 · usefulness score 41/100
• TDP-43 mediates degeneration in a novel Drosophila model of disease caused by mutations in VCP/p97 The Journal of neuroscience : the official journal of the Society for Neuroscience · 2010-06-01 · usefulness score 48/100
• TDP-43 oxidation and PP1 crosstalk at RNA granule-mitochondria contact sites Nature Communications · 2026-06-05 · usefulness score 41/100

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