TFEB overexpression alleviates autophagy-lysosomal deficits caused by progranulin insufficiency
Abstract Progranulin is a pro-protein that is necessary for maintaining lysosomal function. Loss-of-function progranulin (GRN) mutations are a dominant cause of frontotemporal dementia (FTD). Brains of people with FTD due to GRN mutations accumulate lysosomal storage material and exhibit increased e...
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Nature Portfolio
2025-07-01
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| Online Access: | https://doi.org/10.1038/s41598-025-12268-0 |
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| author | Wren O. Nader Kaylan S. Brown Nicholas R. Boyle Azariah K. Kaplelach Shaimaa M. Abdelaziz Skylar E. Davis Qays Aljabi Ahmad R. Hakim Amelia G. Davidson Giacynta A. Vollmer Leah C. Wright J. Bailey Echols Joelle Saad Nicholas S. Pena Andrew E. Arrant |
| author_facet | Wren O. Nader Kaylan S. Brown Nicholas R. Boyle Azariah K. Kaplelach Shaimaa M. Abdelaziz Skylar E. Davis Qays Aljabi Ahmad R. Hakim Amelia G. Davidson Giacynta A. Vollmer Leah C. Wright J. Bailey Echols Joelle Saad Nicholas S. Pena Andrew E. Arrant |
| author_sort | Wren O. Nader |
| collection | DOAJ |
| description | Abstract Progranulin is a pro-protein that is necessary for maintaining lysosomal function. Loss-of-function progranulin (GRN) mutations are a dominant cause of frontotemporal dementia (FTD). Brains of people with FTD due to GRN mutations accumulate lysosomal storage material and exhibit increased expression of lysosomal transcripts, which may be driven by TFEB and related transcription factors. While this may be a compensatory response to lysosomal impairment, overproduction of lysosomal proteins may also contribute to FTD pathogenesis. To investigate how TFEB may contribute to disease in people with GRN mutations, we analyzed the effects of TFEB overexpression in progranulin-insufficient cells and mice. We generated GRN knockout HEK-293 cells (GRN KO cells), which exhibited increased nuclear localization of TFEB and expression of lysosomal transcripts, but impaired autophagy. TFEB overexpression in GRN KO cells further increased lysosomal transcripts and partially normalized autophagy. We next injected an AAV vector expressing mouse Tfeb (AAV-TFEB) into the thalamus of Grn –/– mice, which accumulates lysosomal storage material. AAV-TFEB increased lysosomal transcripts and reduced immunoreactivity for SCMAS, a marker of lysosomal storage material, in Grn –/– thalamus. These data show that TFEB activity alleviates some autophagy-lysosomal deficits caused by progranulin insufficiency, suggesting potential utility of lysosome-based therapies for GRN-associated diseases. |
| format | Article |
| id | doaj-art-85d274bca1904cec86991292dbeb060d |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-85d274bca1904cec86991292dbeb060d2025-08-20T03:43:21ZengNature PortfolioScientific Reports2045-23222025-07-0115111410.1038/s41598-025-12268-0TFEB overexpression alleviates autophagy-lysosomal deficits caused by progranulin insufficiencyWren O. Nader0Kaylan S. Brown1Nicholas R. Boyle2Azariah K. Kaplelach3Shaimaa M. Abdelaziz4Skylar E. Davis5Qays Aljabi6Ahmad R. Hakim7Amelia G. Davidson8Giacynta A. Vollmer9Leah C. Wright10J. Bailey Echols11Joelle Saad12Nicholas S. Pena13Andrew E. Arrant14Killion Center for Neurodegeneration and Experimental Therapeutics, Alzheimer’s Disease Center, Evelyn F. McKnight Brain Institute, Department of Neurology, University of Alabama at BirminghamKillion Center for Neurodegeneration and Experimental Therapeutics, Alzheimer’s Disease Center, Evelyn F. McKnight Brain Institute, Department of Neurology, University of Alabama at BirminghamKillion Center for Neurodegeneration and Experimental Therapeutics, Alzheimer’s Disease Center, Evelyn F. McKnight Brain Institute, Department of Neurology, University of Alabama at BirminghamKillion Center for Neurodegeneration and Experimental Therapeutics, Alzheimer’s Disease Center, Evelyn F. McKnight Brain Institute, Department of Neurology, University of Alabama at BirminghamKillion Center for Neurodegeneration and Experimental Therapeutics, Alzheimer’s Disease Center, Evelyn F. McKnight Brain Institute, Department of Neurology, University of Alabama at BirminghamKillion Center for Neurodegeneration and Experimental Therapeutics, Alzheimer’s Disease Center, Evelyn F. McKnight Brain Institute, Department of Neurology, University of Alabama at BirminghamKillion Center for Neurodegeneration and Experimental Therapeutics, Alzheimer’s Disease Center, Evelyn F. McKnight Brain Institute, Department of Neurology, University of Alabama at BirminghamKillion Center for Neurodegeneration and Experimental Therapeutics, Alzheimer’s Disease Center, Evelyn F. McKnight Brain Institute, Department of Neurology, University of Alabama at BirminghamKillion Center for Neurodegeneration and Experimental Therapeutics, Alzheimer’s Disease Center, Evelyn F. McKnight Brain Institute, Department of Neurology, University of Alabama at BirminghamKillion Center for Neurodegeneration and Experimental Therapeutics, Alzheimer’s Disease Center, Evelyn F. McKnight Brain Institute, Department of Neurology, University of Alabama at BirminghamKillion Center for Neurodegeneration and Experimental Therapeutics, Alzheimer’s Disease Center, Evelyn F. McKnight Brain Institute, Department of Neurology, University of Alabama at BirminghamKillion Center for Neurodegeneration and Experimental Therapeutics, Alzheimer’s Disease Center, Evelyn F. McKnight Brain Institute, Department of Neurology, University of Alabama at BirminghamKillion Center for Neurodegeneration and Experimental Therapeutics, Alzheimer’s Disease Center, Evelyn F. McKnight Brain Institute, Department of Neurology, University of Alabama at BirminghamKillion Center for Neurodegeneration and Experimental Therapeutics, Alzheimer’s Disease Center, Evelyn F. McKnight Brain Institute, Department of Neurology, University of Alabama at BirminghamKillion Center for Neurodegeneration and Experimental Therapeutics, Alzheimer’s Disease Center, Evelyn F. McKnight Brain Institute, Department of Neurology, University of Alabama at BirminghamAbstract Progranulin is a pro-protein that is necessary for maintaining lysosomal function. Loss-of-function progranulin (GRN) mutations are a dominant cause of frontotemporal dementia (FTD). Brains of people with FTD due to GRN mutations accumulate lysosomal storage material and exhibit increased expression of lysosomal transcripts, which may be driven by TFEB and related transcription factors. While this may be a compensatory response to lysosomal impairment, overproduction of lysosomal proteins may also contribute to FTD pathogenesis. To investigate how TFEB may contribute to disease in people with GRN mutations, we analyzed the effects of TFEB overexpression in progranulin-insufficient cells and mice. We generated GRN knockout HEK-293 cells (GRN KO cells), which exhibited increased nuclear localization of TFEB and expression of lysosomal transcripts, but impaired autophagy. TFEB overexpression in GRN KO cells further increased lysosomal transcripts and partially normalized autophagy. We next injected an AAV vector expressing mouse Tfeb (AAV-TFEB) into the thalamus of Grn –/– mice, which accumulates lysosomal storage material. AAV-TFEB increased lysosomal transcripts and reduced immunoreactivity for SCMAS, a marker of lysosomal storage material, in Grn –/– thalamus. These data show that TFEB activity alleviates some autophagy-lysosomal deficits caused by progranulin insufficiency, suggesting potential utility of lysosome-based therapies for GRN-associated diseases.https://doi.org/10.1038/s41598-025-12268-0ProgranulinTFEBLysosomesAutophagy |
| spellingShingle | Wren O. Nader Kaylan S. Brown Nicholas R. Boyle Azariah K. Kaplelach Shaimaa M. Abdelaziz Skylar E. Davis Qays Aljabi Ahmad R. Hakim Amelia G. Davidson Giacynta A. Vollmer Leah C. Wright J. Bailey Echols Joelle Saad Nicholas S. Pena Andrew E. Arrant TFEB overexpression alleviates autophagy-lysosomal deficits caused by progranulin insufficiency Scientific Reports Progranulin TFEB Lysosomes Autophagy |
| title | TFEB overexpression alleviates autophagy-lysosomal deficits caused by progranulin insufficiency |
| title_full | TFEB overexpression alleviates autophagy-lysosomal deficits caused by progranulin insufficiency |
| title_fullStr | TFEB overexpression alleviates autophagy-lysosomal deficits caused by progranulin insufficiency |
| title_full_unstemmed | TFEB overexpression alleviates autophagy-lysosomal deficits caused by progranulin insufficiency |
| title_short | TFEB overexpression alleviates autophagy-lysosomal deficits caused by progranulin insufficiency |
| title_sort | tfeb overexpression alleviates autophagy lysosomal deficits caused by progranulin insufficiency |
| topic | Progranulin TFEB Lysosomes Autophagy |
| url | https://doi.org/10.1038/s41598-025-12268-0 |
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