Reduction 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...
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| Language: | English |
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Elsevier
2025-09-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125002402 |
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| author | Nicholas R. Boyle Stephanie N. Fox Aniketh S. Tadepalli Nicholas T. Seyfried Thomas Kukar Eliana M. Ramos Alissa L. Nana Salvatore Spina Lea T. Grinberg Bruce L. Miller William W. Seeley Andrew E. Arrant Erik D. Roberson |
| author_facet | Nicholas R. Boyle Stephanie N. Fox Aniketh S. Tadepalli Nicholas T. Seyfried Thomas Kukar Eliana M. Ramos Alissa L. Nana Salvatore Spina Lea T. Grinberg Bruce L. Miller William W. Seeley Andrew E. Arrant Erik D. Roberson |
| author_sort | Nicholas R. Boyle |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-43f5e49acabc481284314d878f7fc7ec |
| institution | DOAJ |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
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| series | Neurobiology of Disease |
| spelling | doaj-art-43f5e49acabc481284314d878f7fc7ec2025-08-20T02:45:42ZengElsevierNeurobiology of Disease1095-953X2025-09-0121310702410.1016/j.nbd.2025.107024Reduction of sphingomyelinase activity associated with progranulin deficiency and frontotemporal dementiaNicholas R. Boyle0Stephanie N. Fox1Aniketh S. Tadepalli2Nicholas T. Seyfried3Thomas Kukar4Eliana M. Ramos5Alissa L. Nana6Salvatore Spina7Lea T. Grinberg8Bruce L. Miller9William W. Seeley10Andrew E. Arrant11Erik D. Roberson12Department of Neurology, Killion Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, University of Alabama at Birmingham, Birmingham, AL, USADepartment of Neurology, Killion Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, University of Alabama at Birmingham, Birmingham, AL, USADepartment of Neurology, Killion Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, University of Alabama at Birmingham, Birmingham, AL, USADepartment of Biochemistry, School of Medicine, Emory University, Atlanta, GA, USADepartment of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, GA, USADepartment of Psychiatry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USADepartment of Neurology, Memory & Aging Center, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USADepartment of Neurology, Memory & Aging Center, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USADepartment of Neurology, Memory & Aging Center, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA; Department of Pathology, University of California, San Francisco, CA, USADepartment of Neurology, Memory & Aging Center, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USADepartment of Neurology, Memory & Aging Center, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA; Department of Pathology, University of California, San Francisco, CA, USADepartment of Neurology, Killion Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, University of Alabama at Birmingham, Birmingham, AL, USADepartment of Neurology, Killion Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, University of Alabama at Birmingham, Birmingham, AL, USA; Corresponding author at: Shelby Biomedical Research Building 1110, 1825 University Blvd, Birmingham, AL 35294, USA.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.http://www.sciencedirect.com/science/article/pii/S0969996125002402Frontotemporal dementiaFrontotemporal lobar degenerationProgranulinSphingomyelinaseSphingolipidLysosome |
| spellingShingle | Nicholas R. Boyle Stephanie N. Fox Aniketh S. Tadepalli Nicholas T. Seyfried Thomas Kukar Eliana M. Ramos Alissa L. Nana Salvatore Spina Lea T. Grinberg Bruce L. Miller William W. Seeley Andrew E. Arrant Erik D. Roberson Reduction of sphingomyelinase activity associated with progranulin deficiency and frontotemporal dementia Neurobiology of Disease Frontotemporal dementia Frontotemporal lobar degeneration Progranulin Sphingomyelinase Sphingolipid Lysosome |
| title | Reduction of sphingomyelinase activity associated with progranulin deficiency and frontotemporal dementia |
| title_full | Reduction of sphingomyelinase activity associated with progranulin deficiency and frontotemporal dementia |
| title_fullStr | Reduction of sphingomyelinase activity associated with progranulin deficiency and frontotemporal dementia |
| title_full_unstemmed | Reduction of sphingomyelinase activity associated with progranulin deficiency and frontotemporal dementia |
| title_short | Reduction of sphingomyelinase activity associated with progranulin deficiency and frontotemporal dementia |
| title_sort | reduction of sphingomyelinase activity associated with progranulin deficiency and frontotemporal dementia |
| topic | Frontotemporal dementia Frontotemporal lobar degeneration Progranulin Sphingomyelinase Sphingolipid Lysosome |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125002402 |
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