biostudies-literatureBoyle NRNIA NIH HHSNINDS NIH HHS107024https://www.ebi.ac.uk/biostudies/studies/S-EPMC12320091biostudies-literatureUnknown213Loss-of-function mutations affecting the lysosomal protein progranulin are a leading cause of frontotemporal dementia. Progranulin mutations cause abnormalities in lysosomal lipid processing, particularly of sphingolipids, major components of neural cell membranes that play important signaling roles in the brain. Most work in this area has focused on two classes of sphingolipids, gangliosides and cerebrosides. Here, we examined enzymes involved in metabolism of another class of sphingolipids, the sphingomyelins, in both mouse models and patients with progranulin insufficiency. Acidic sphingomyelinase activity was decreased in progranulin knockout, but not heterozygous, mice. This resulted from post-transcriptional loss of acid sphingomyelinase (Smpd1) protein. Progranulin interacted with aNeurobiology of diseaseReduction of sphingomyelinase activity associated with progranulin deficiency and frontotemporal dementia.PMC12320091K00 AG068428P30 AG086401P30 AG062422P01 AG019724R00 AG056597RF1 AG079318F30 AG071114R01 NS105971Miller BLNana ALBoyle NRGrinberg LTTadepalli ASRamos EMFox SNArrant AERoberson EDKukar TSpina SSeyfried NTSeeley WWfalseReduction of sphingomyelinase activity associated with progranulin deficiency and frontotemporal dementia.Loss-of-function mutations affecting the lysosomal protein progranulin are a leading cause of frontotemporal dementia. Progranulin mutations cause abnormalities in lysosomal lipid processing, particularly of sphingolipids, major components of neural cell membranes that play important signaling roles in the brain. Most work in this area has focused on two classes of sphingolipids, gangliosides and cerebrosides. Here, we examined enzymes involved in metabolism of another class of sphingolipids, the sphingomyelins, in both mouse models and patients with progranulin insufficiency. Acidic sphingomyelinase activity was decreased in progranulin knockout, but not heterozygous, mice. This resulted from post-transcriptional loss of acid sphingomyelinase (Smpd1) protein. Progranulin interacted with a2025-01-01T00:00:00Z2025 Sep2026-03-31T11:56:19.043Z2025-09-01T03:08:24.347ZS-EPMC123200914063367910.1016/j.nbd.2025.107024