Cerebral organoids derived from Sandhoff disease-induced pluripotent stem cells exhibit impaired neurodifferentiation[S]
Sandhoff disease, one of the GM2 gangliosidoses, is a lysosomal storage disorder characterized by the absence of β-hexosaminidase A and B activity and the concomitant lysosomal accumulation of its substrate, GM2 ganglioside. It features catastrophic neurodegeneration and death in early childhood. Ho...
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| Format: | Article |
| Language: | English |
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Elsevier
2018-03-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520331424 |
| _version_ | 1823943145406070784 |
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| author | Maria L. Allende Emily K. Cook Bridget C. Larman Adrienne Nugent Jacqueline M. Brady Diane Golebiowski Miguel Sena-Esteves Cynthia J. Tifft Richard L. Proia |
| author_facet | Maria L. Allende Emily K. Cook Bridget C. Larman Adrienne Nugent Jacqueline M. Brady Diane Golebiowski Miguel Sena-Esteves Cynthia J. Tifft Richard L. Proia |
| author_sort | Maria L. Allende |
| collection | DOAJ |
| description | Sandhoff disease, one of the GM2 gangliosidoses, is a lysosomal storage disorder characterized by the absence of β-hexosaminidase A and B activity and the concomitant lysosomal accumulation of its substrate, GM2 ganglioside. It features catastrophic neurodegeneration and death in early childhood. How the lysosomal accumulation of ganglioside might affect the early development of the nervous system is not understood. Recently, cerebral organoids derived from induced pluripotent stem (iPS) cells have illuminated early developmental events altered by disease processes. To develop an early neurodevelopmental model of Sandhoff disease, we first generated iPS cells from the fibroblasts of an infantile Sandhoff disease patient, then corrected one of the mutant HEXB alleles in those iPS cells using CRISPR/Cas9 genome-editing technology, thereby creating isogenic controls. Next, we used the parental Sandhoff disease iPS cells and isogenic HEXB-corrected iPS cell clones to generate cerebral organoids that modeled the first trimester of neurodevelopment. The Sandhoff disease organoids, but not the HEXB-corrected organoids, accumulated GM2 ganglioside and exhibited increased size and cellular proliferation compared with the HEXB-corrected organoids. Whole-transcriptome analysis demonstrated that development was impaired in the Sandhoff disease organoids, suggesting that alterations in neuronal differentiation may occur during early development in the GM2 gangliosidoses. |
| first_indexed | 2024-12-17T04:46:57Z |
| format | Article |
| id | doaj.art-92b131018d354437940c5128314b85f9 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-17T04:46:57Z |
| publishDate | 2018-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-92b131018d354437940c5128314b85f92022-12-21T22:03:02ZengElsevierJournal of Lipid Research0022-22752018-03-01593550563Cerebral organoids derived from Sandhoff disease-induced pluripotent stem cells exhibit impaired neurodifferentiation[S]Maria L. Allende0Emily K. Cook1Bridget C. Larman2Adrienne Nugent3Jacqueline M. Brady4Diane Golebiowski5Miguel Sena-Esteves6Cynthia J. Tifft7Richard L. Proia8Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892National Institutes of Health Undiagnosed Diseases Program, National Institutes of Health Office of Rare Diseases Research and National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892Department of Neurology and Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605Department of Neurology and Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605National Institutes of Health Undiagnosed Diseases Program, National Institutes of Health Office of Rare Diseases Research and National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; To whom correspondence should be addressed.Sandhoff disease, one of the GM2 gangliosidoses, is a lysosomal storage disorder characterized by the absence of β-hexosaminidase A and B activity and the concomitant lysosomal accumulation of its substrate, GM2 ganglioside. It features catastrophic neurodegeneration and death in early childhood. How the lysosomal accumulation of ganglioside might affect the early development of the nervous system is not understood. Recently, cerebral organoids derived from induced pluripotent stem (iPS) cells have illuminated early developmental events altered by disease processes. To develop an early neurodevelopmental model of Sandhoff disease, we first generated iPS cells from the fibroblasts of an infantile Sandhoff disease patient, then corrected one of the mutant HEXB alleles in those iPS cells using CRISPR/Cas9 genome-editing technology, thereby creating isogenic controls. Next, we used the parental Sandhoff disease iPS cells and isogenic HEXB-corrected iPS cell clones to generate cerebral organoids that modeled the first trimester of neurodevelopment. The Sandhoff disease organoids, but not the HEXB-corrected organoids, accumulated GM2 ganglioside and exhibited increased size and cellular proliferation compared with the HEXB-corrected organoids. Whole-transcriptome analysis demonstrated that development was impaired in the Sandhoff disease organoids, suggesting that alterations in neuronal differentiation may occur during early development in the GM2 gangliosidoses.http://www.sciencedirect.com/science/article/pii/S0022227520331424storage diseasesgangliosidesTay-Sachs diseasesphingolipidsbrain lipidsClustered Regularly Interspaced Short Palindromic Repeats/Cas9 |
| spellingShingle | Maria L. Allende Emily K. Cook Bridget C. Larman Adrienne Nugent Jacqueline M. Brady Diane Golebiowski Miguel Sena-Esteves Cynthia J. Tifft Richard L. Proia Cerebral organoids derived from Sandhoff disease-induced pluripotent stem cells exhibit impaired neurodifferentiation[S] Journal of Lipid Research storage diseases gangliosides Tay-Sachs disease sphingolipids brain lipids Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 |
| title | Cerebral organoids derived from Sandhoff disease-induced pluripotent stem cells exhibit impaired neurodifferentiation[S] |
| title_full | Cerebral organoids derived from Sandhoff disease-induced pluripotent stem cells exhibit impaired neurodifferentiation[S] |
| title_fullStr | Cerebral organoids derived from Sandhoff disease-induced pluripotent stem cells exhibit impaired neurodifferentiation[S] |
| title_full_unstemmed | Cerebral organoids derived from Sandhoff disease-induced pluripotent stem cells exhibit impaired neurodifferentiation[S] |
| title_short | Cerebral organoids derived from Sandhoff disease-induced pluripotent stem cells exhibit impaired neurodifferentiation[S] |
| title_sort | cerebral organoids derived from sandhoff disease induced pluripotent stem cells exhibit impaired neurodifferentiation s |
| topic | storage diseases gangliosides Tay-Sachs disease sphingolipids brain lipids Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520331424 |
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