• Kozo Matsushita, Tadahiro Numakawa, Haruki Odaka, Ryutaro Kajihara, Minami Soga, Shiro Ozasa, Kimitoshi Nakamura, Hiroshi Mizuta, and Takumi Era.
• Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan; Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
• Neuroscience. 2019 Aug 21; 414: 128-140.

AbstractTay-Sachs disease (TSD) is a GM2 gangliosidosis lysosomal storage disease caused by a loss of lysosomal hexosaminidase-A (HEXA) activity and characterized by progressive neurodegeneration due to the massive accumulation of GM2 ganglioside in the brain. Here, we generated iPSCs derived from patients with TSD, and found similar potential for neural differentiation between TSD-iPSCs and normal iPSCs, although neural progenitor cells (NPCs) derived from the TSD-iPSCs exhibited enlarged lysosomes and upregulation of the lysosomal marker, LAMP1, caused by the accumulation of GM2 ganglioside. The NPCs derived from TSD-iPSCs also had an increased incidence of oxidative stress-induced cell death. TSD-iPSC-derived neurons showed a decrease in exocytotic activity with the accumulation of GM2 ganglioside, suggesting deficient neurotransmission in TSD. Our findings demonstrated that NPCs and mature neurons derived from TSD-iPSCs are potentially useful cellular models of TSD and are useful for investigating the efficacy of drug candidates in the future.Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.

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