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

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. Despite observing no change in TDP-43 aggregation with Grn genotype in hTDP+ or hTDP++ mice, we found that human TDP-43 expression worsened FTD-related phenotypes in progranulin-insufficient mice. Human TDP-43 expression worsened social dominance behavior in Grn+/− mice, which was associated with dendritic spine abnormalities in medial prefrontal cortex (mPFC). Human TDP-43 also had distinct effects on RNA splicing in frontal cortex of Grn+/− versus wild-type mice. All hTDP++ mice developed severe motor deficits and neuroinflammation. However, human TDP-43 expression induced worse motor deficits in Grn−/−:hTDP++ mice, as well as an abnormal inflammatory 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.