Human TDP-43 expression worsens FTD-related phenotypes in progranulin-insufficient mice

Topic: Brain proteins, microglia and lab models

Loss-of-function progranulin ( GRN ) mutations cause frontotemporal dementia with TDP-43 pathology (FTD-TDP). Nearly all pathogenic GRN mutations cause progranulin haploinsufficiency, but it is unclear how progranulin insufficiency causes FTD-TDP. To address this question, we crossed progranulin-insufficient mice with a human TDP-43 transgenic mouse line (RRID:IMSR_JAX:012836) in which homozygous mice (hTDP++) develop TDP-43 aggregates at an early age, but hemizygous mice (hTDP+) do not TDP-43 aggregates. We therefore analyzed the effects of progranulin insufficiency on both hTDP+ and hTDP++ mice. Progranulin insufficiency did not induce TDP-43 aggregation in hTDP+ mice, but interacted with hTDP expression to worsened FTD-related phenotypes. Grn +/− :hTDP+ mice exhibited more dramatic impairment of social dominance than either Grn +/− or hTDP+ mice, which was associated with combined effects of progranulin insufficiency and hTDP expression on dendritic spines of neurons in the medial prefrontal cortex (mPFC). Despite a lack of TDP-43 aggregation, progranulin insufficiency altered the RNA splicing events induced by hTDP overexpression in frontal cortex of hTDP+ mice. Progranulin insufficiency also did not alter TDP-43 aggregation in hTDP++ mice, but Grn −/− :hTDP++ mice exhibited an abnormal neuroinflammatory response characterized by increased markers of disease-associated microglia and signs of an impaired adaptive immune response. These results highlight dysfunction of mPFC neurons as a potential mechanism of behavioral changes in FTD- GRN , and implicate dysregulated inflammation as a potential driver of disease progression in FTD- GRN .

Key findings

• Grn +/− :hTDP+ mice exhibited more dramatic impairment of social dominance than either Grn +/− or hTDP+ mice, which was associated with combined effects of progranulin insufficiency and hTDP expression on dendritic spines of neurons in the medial prefrontal cortex (mPFC).
• These results highlight dysfunction of mPFC neurons as a potential mechanism of behavioral changes in FTD- GRN , and implicate dysregulated inflammation as a potential driver of disease progression in FTD- GRN .

Why it matters

In mice with progranulin insufficiency crossed with human TDP-43 transgenic mice, progranulin insufficiency did not induce TDP-43 aggregation but worsened FTD-related phenotypes and altered RNA splicing. These results highlight dysfunction of mPFC neurons and dysregulated inflammation as potential drivers of disease progression in FTD-GRN, but the work is in mice.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1016/j.nbd.2026.107475
• PubMed: 42264399
• Original source →
• Free full text: Neurobiology of Disease →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{cook2026-42264399,
  author  = {Cook, Anna K. and Lin, Benjamin and Song, Yumo and Greathouse, Kelsey M. and Kaplelach, Azariah K. and Love, Mackenzie L. and Davis, Skylar E. and Stoll, Anna C. and others},
  title   = {{Human TDP-43 expression worsens FTD-related phenotypes in progranulin-insufficient mice}},
  journal = {Neurobiology of Disease},
  year    = {2026},
  doi     = {10.1016/j.nbd.2026.107475},
  pmid    = {42264399},
  url     = {https://doi.org/10.1016/j.nbd.2026.107475}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 24.

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• Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration Cell · 2018-05-01 · usefulness score 58/100 · TREM2 and immune genetics
• TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD Science (New York, N.Y.) · 2015-08-01 · usefulness score 57/100 · Lewy body dementia
• Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation Cell · 2016-04-21 · usefulness score 57/100 · Lewy body dementia
• Plasma glial fibrillary acidic protein is raised in progranulin-associated frontotemporal dementia Journal of neurology, neurosurgery, and psychiatry · 2020-01-14 · usefulness score 57/100 · Cognitive tests and assessment
• TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Biochemical and biophysical research communications · 2006-10-30 · usefulness score 56/100 · Lewy body dementia
• TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD Nature neuroscience · 2018-03-19 · usefulness score 56/100 · Brain tissue and pathology

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