title: Impaired neural differentiation of induced pluripotent stem cells generated from a mouse model of Sandhoff disease.
abstract: Sandhoff disease (SD) is a glycosphingolipid storage disease that arises from mutations in the Hexb gene and the resultant deficiency in β-hexosaminidase activity. This deficiency results in aberrant lysosomal accumulation of the ganglioside GM2 and related glycolipids, and progressive deterioration of the central nervous system. Dysfunctional glycolipid storage causes severe neurodegeneration through a poorly understood pathogenic mechanism. Induced pluripotent stem cell (iPSC) technology offers new opportunities for both elucidation of the pathogenesis of diseases and the development of stem cell-based therapies. Here, we report the generation of disease-specific iPSCs from a mouse model of SD. These mouse model-derived iPSCs (SD-iPSCs) exhibited pluripotent stem cell properties and significant accumulation of GM2 ganglioside. In lineage-directed differentiation studies using the stromal cell-derived inducing activity method, SD-iPSCs showed an impaired ability to differentiate into early stage neural precursors. Moreover, fewer neurons differentiated from neural precursors in SD-iPSCs than in the case of the wild type. Recovery of the Hexb gene in SD-iPSCs improved this impairment of neuronal differentiation. These results provide new insights as to understanding the complex pathogenic mechanisms of SD.
authors: Department of Pharmacology, Meiji Pharmaceutical University, Tokyo, Japan.
authors: Yasuhiro
authors: Y
authors: Ogawa
authors: Makoto
authors: M
authors: Tanaka
authors: Miho
authors: M
authors: Tanabe
authors: Toshihiro
authors: T
authors: Suzuki
authors: Tadayasu
authors: T
authors: Togawa
authors: Tomoko
authors: T
authors: Fukushige
authors: Takuro
authors: T
authors: Kanekura
authors: Hitoshi
authors: H
authors: Sakuraba
authors: Kazuhiko
authors: K
authors: Oishi
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D004195:Disease Models, Animal; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D010641:Phenotype; D012497:Sandhoff Disease / Q000209:etiology* / Q000235:genetics; D054821:beta-Hexosaminidase beta Chain / Q000235:genetics / Q000378:metabolism
chemical_list: D054821:beta-Hexosaminidase beta Chain
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