Reactivation of mTOR signaling slows neurodegeneration in a lysosomal sphingolipid storage disease
Sandhoff disease, a lysosomal storage disorder, is caused by pathogenic variants in the HEXB gene, resulting in the loss of β-hexosaminidase activity and accumulation of sphingolipids including GM2 ganglioside. This accumulation occurs primarily in neurons, and leads to progressive neurodegeneration...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-01-01
|
| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996124003620 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841556978633015296 |
|---|---|
| author | Hongling Zhu Y. Terry Lee Colleen Byrnes Jabili Angina Danielle A. Springer Galina Tuymetova Mari Kono Cynthia J. Tifft Richard L. Proia |
| author_facet | Hongling Zhu Y. Terry Lee Colleen Byrnes Jabili Angina Danielle A. Springer Galina Tuymetova Mari Kono Cynthia J. Tifft Richard L. Proia |
| author_sort | Hongling Zhu |
| collection | DOAJ |
| description | Sandhoff disease, a lysosomal storage disorder, is caused by pathogenic variants in the HEXB gene, resulting in the loss of β-hexosaminidase activity and accumulation of sphingolipids including GM2 ganglioside. This accumulation occurs primarily in neurons, and leads to progressive neurodegeneration through a largely unknown process. Lysosomal storage diseases often exhibit dysfunctional mTOR signaling, a pathway crucial for proper neuronal development and function. In this study, Sandhoff disease model mice exhibited reduced mTOR signaling in the brain. To test if restoring mTOR signaling could improve the disease phenotype, we genetically reduced expression of the mTOR inhibitor Tsc2 in these mice. Sandhoff disease mice with reactivated mTOR signaling displayed increased survival rates and motor function, especially in females, increased dendritic-spine density, and reduced neurodegeneration. Tsc2 reduction also partially rescued aberrant synaptic function–related gene expression. These findings imply that enhancing mTOR signaling could be a potential therapeutic strategy for lysosomal-based neurodegenerative diseases. |
| format | Article |
| id | doaj-art-e66d4b89107643818bec8e63598b4b1b |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-e66d4b89107643818bec8e63598b4b1b2025-01-07T04:17:07ZengElsevierNeurobiology of Disease1095-953X2025-01-01204106760Reactivation of mTOR signaling slows neurodegeneration in a lysosomal sphingolipid storage diseaseHongling Zhu0Y. Terry Lee1Colleen Byrnes2Jabili Angina3Danielle A. Springer4Galina Tuymetova5Mari Kono6Cynthia J. Tifft7Richard L. Proia8Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USAGenetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USAGenetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USAGenetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USAMurine Phenotyping Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USAGenetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USAGenetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USAMedical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USAGenetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA; Corresponding author.Sandhoff disease, a lysosomal storage disorder, is caused by pathogenic variants in the HEXB gene, resulting in the loss of β-hexosaminidase activity and accumulation of sphingolipids including GM2 ganglioside. This accumulation occurs primarily in neurons, and leads to progressive neurodegeneration through a largely unknown process. Lysosomal storage diseases often exhibit dysfunctional mTOR signaling, a pathway crucial for proper neuronal development and function. In this study, Sandhoff disease model mice exhibited reduced mTOR signaling in the brain. To test if restoring mTOR signaling could improve the disease phenotype, we genetically reduced expression of the mTOR inhibitor Tsc2 in these mice. Sandhoff disease mice with reactivated mTOR signaling displayed increased survival rates and motor function, especially in females, increased dendritic-spine density, and reduced neurodegeneration. Tsc2 reduction also partially rescued aberrant synaptic function–related gene expression. These findings imply that enhancing mTOR signaling could be a potential therapeutic strategy for lysosomal-based neurodegenerative diseases.http://www.sciencedirect.com/science/article/pii/S0969996124003620SphingolipidNeurodegenerationmTORLysosomeGangliosideSandhoff disease |
| spellingShingle | Hongling Zhu Y. Terry Lee Colleen Byrnes Jabili Angina Danielle A. Springer Galina Tuymetova Mari Kono Cynthia J. Tifft Richard L. Proia Reactivation of mTOR signaling slows neurodegeneration in a lysosomal sphingolipid storage disease Neurobiology of Disease Sphingolipid Neurodegeneration mTOR Lysosome Ganglioside Sandhoff disease |
| title | Reactivation of mTOR signaling slows neurodegeneration in a lysosomal sphingolipid storage disease |
| title_full | Reactivation of mTOR signaling slows neurodegeneration in a lysosomal sphingolipid storage disease |
| title_fullStr | Reactivation of mTOR signaling slows neurodegeneration in a lysosomal sphingolipid storage disease |
| title_full_unstemmed | Reactivation of mTOR signaling slows neurodegeneration in a lysosomal sphingolipid storage disease |
| title_short | Reactivation of mTOR signaling slows neurodegeneration in a lysosomal sphingolipid storage disease |
| title_sort | reactivation of mtor signaling slows neurodegeneration in a lysosomal sphingolipid storage disease |
| topic | Sphingolipid Neurodegeneration mTOR Lysosome Ganglioside Sandhoff disease |
| url | http://www.sciencedirect.com/science/article/pii/S0969996124003620 |
| work_keys_str_mv | AT honglingzhu reactivationofmtorsignalingslowsneurodegenerationinalysosomalsphingolipidstoragedisease AT yterrylee reactivationofmtorsignalingslowsneurodegenerationinalysosomalsphingolipidstoragedisease AT colleenbyrnes reactivationofmtorsignalingslowsneurodegenerationinalysosomalsphingolipidstoragedisease AT jabiliangina reactivationofmtorsignalingslowsneurodegenerationinalysosomalsphingolipidstoragedisease AT danielleaspringer reactivationofmtorsignalingslowsneurodegenerationinalysosomalsphingolipidstoragedisease AT galinatuymetova reactivationofmtorsignalingslowsneurodegenerationinalysosomalsphingolipidstoragedisease AT marikono reactivationofmtorsignalingslowsneurodegenerationinalysosomalsphingolipidstoragedisease AT cynthiajtifft reactivationofmtorsignalingslowsneurodegenerationinalysosomalsphingolipidstoragedisease AT richardlproia reactivationofmtorsignalingslowsneurodegenerationinalysosomalsphingolipidstoragedisease |