Cerebral organoids derived from Sandhoff disease-induced pluripotent stem cells exhibit impaired neurodifferentiation
AuthorsAllende, Maria L.
Cook, Emily K.
Larman, Bridget C.
Brady, Jacqueline M.
Tifft, Cynthia J.
Proia, Richard L.
UMass Chan AffiliationsHorae Gene Therapy Center
Department of Neurology
Document TypeJournal Article
KeywordsClustered Regularly Interspaced Short Palindromic Repeats/Cas9
patient-derived induced pluripotent stem cells
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Nervous System Diseases
Neuroscience and Neurobiology
Nutritional and Metabolic Diseases
MetadataShow full item record
AbstractSandhoff disease, one of the GM2 gangliosidoses, is a lysosomal storage disorder characterized by the absence of beta-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.
J Lipid Res. 2018 Mar;59(3):550-563. doi: 10.1194/jlr.M081323. Epub 2018 Jan 22. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/40546
RightsOpen Access Author’s Choice—Final version free via Creative Commons CC-BY license.
Except where otherwise noted, this item's license is described as Open Access Author’s Choice—Final version free via Creative Commons CC-BY license.
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