Reduction of sphingomyelinase activity associated with progranulin deficiency and frontotemporal dementia

Topic: Brain proteins, microglia and lab models

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 acid sphingomyelinase in immunoprecipitation and proximity ligation assays, suggesting a co-trafficking role like progranulin plays with other lysosomal enzymes. Consistent with that hypothesis, restoring progranulin in knockout mice using AAV-progranulin gene therapy corrected acid sphingomyelinase deficits. In post-mortem brain tissue from patients with frontotemporal dementia due to heterozygous progranulin mutations, neutral, but not acidic, sphingomyelinase activity was decreased. Neutral sphingomyelinase 2 (SMPD3), the predominant neutral sphingomyelinase in the brain, was reduced in patients with progranulin mutations. A similar trend ( p = 0.0586) was seen in patients with sporadic frontotemporal lobar degeneration with type A TDP-43 pathology, but not in other types of frontotemporal lobar degeneration. The reduction of neutral sphingomyelinase 2 occurred in frontal, but not occipital cortex, correlating with the selective vulnerability of frontal regions seen in FTD. These data shed light on the role of progranulin in sphingomyelin metabolism and of this pathway in frontotemporal dementia. • Acidic, but not neutral, sphingomyelinase activity is decreased in Grn −/− mice. • AAV-progranulin gene therapy corrects acid sphingomyelinase deficits in Grn −/− mice. • Progranulin interacts with acid, but not neutral sphingomyelinase. • Neutral, but not acidic, sphingomyelinase activity is decreased in FTD- GRN . • nSMase2 is reduced in FTD- GRN and sporadic TDP-A, selectively in affected areas.

Key findings

• In post-mortem brain tissue from patients with frontotemporal dementia due to heterozygous progranulin mutations, neutral, but not acidic, sphingomyelinase activity was decreased.
• Neutral sphingomyelinase 2 (SMPD3), the predominant neutral sphingomyelinase in the brain, was reduced in patients with progranulin mutations.
• A similar trend ( p = 0.0586) was seen in patients with sporadic frontotemporal lobar degeneration with type A TDP-43 pathology, but not in other types of frontotemporal lobar degeneration.
• The reduction of neutral sphingomyelinase 2 occurred in frontal, but not occipital cortex, correlating with the selective vulnerability of frontal regions seen in FTD.
• These data shed light on the role of progranulin in sphingomyelin metabolism and of this pathway in frontotemporal dementia. • Acidic, but not neutral, sphingomyelinase activity is decreased in Grn −/− mice. • AAV-progranulin gene therapy corrects acid sphingomyelinase deficits in Grn −/− mice. • Progranulin interacts with acid, but not neutral sphingomyelinase. • Neutral, but not acidic, sphingomyelinase activity is decreased in FTD- GRN . • nSMase2 is reduced in FTD- GRN and sporadic TDP-A, selectively in affected areas.

Why it matters

In mice lacking progranulin, acid sphingomyelinase activity was reduced, and restoring progranulin with gene therapy corrected this deficit. In brain tissue from patients with progranulin mutations, a different enzyme, neutral sphingomyelinase, was reduced instead, so it is not yet clear how these findings could be used to treat frontotemporal dementia.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1016/j.nbd.2025.107024
• PubMed: 40633679
• 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{boyle2025-40633679,
  author  = {Boyle, Nicholas R. and Fox, Stephanie N. and Tadepalli, Aniketh S. and Seyfried, Nicholas T. and Kukar, Thomas L. and Ramos, Eliana Marisa and Nana, Alissa L. and Spina, Salvatore and others},
  title   = {{Reduction of sphingomyelinase activity associated with progranulin deficiency and frontotemporal dementia}},
  journal = {Neurobiology of Disease},
  year    = {2025},
  doi     = {10.1016/j.nbd.2025.107024},
  pmid    = {40633679},
  url     = {https://doi.org/10.1016/j.nbd.2025.107024}
}

Studies this one cites

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

• TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A Nature · 2022-02-23 · usefulness score 64/100 · Lewy body dementia
• Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17 Nature · 2006-07-16 · usefulness score 61/100 · Lewy body dementia
• Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage American journal of human genetics · 2012-05-17 · usefulness score 53/100 · Lewy body dementia
• Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic Cell · 2021-08-26 · usefulness score 53/100 · Inflammation and the immune system
• Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury The Journal of clinical investigation · 2012-10-08 · usefulness score 50/100 · Inflammation and the immune system
• Exosome secretion is a key pathway for clearance of pathological TDP-43 Brain : a journal of neurology · 2016-09-27 · usefulness score 50/100 · Lewy body dementia

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• Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21 Nature · 2006-07-16 · usefulness score 64/100
• Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members Brain : a journal of neurology · 2009-01-21 · usefulness score 60/100

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