<p>The progranulin (PGRN) protein is tightly linked with TDP-43 proteinopathy in neurodegenerative diseases. However, how PGRN regulates TDP-43 proteinopathy remains unclear. In this study, we investigated the effect of PGRN loss on TDP-43 pathology in the TDP-43^Q331K knock-in mice expressing an ALS-linked TDP-43 mutation at the endogenous level, and in the transgenic mice overexpressing human TDP-43 in neurons. We found that PGRN deficiency leads to mild glial activation and behavioral deficits in TDP-43^Q331K mice without inducing typical TDP-43 pathology. RNA-seq analysis reveals upregulation of immune pathways and downregulation of myelination-related pathways in PGRN-deficient TDP-43^Q331K mice. In addition, we observed myelination defects in human TDP-43 transgenic mice, but PGRN loss does not exacerbate TDP-43 pathology, myelination defects, and motor deficits in this mouse strain. Our studies demonstrated that PGRN deficiency exacerbates behavioral deficits and glial pathology caused by TDP-43 Q331K mutation but has minimal effect on TDP-43 pathology in mouse models.</p>