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KMID : 0918520200200010001
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Journal of the Korean Society of Inherited Metabolic Disease
2020 Volume.20 No. 1 p.1 ~ p.13
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Inhibitory Action of a Histone Deacetylase 6 Inhibitor on Glucosylceramide- and Glucosylsphingosine-induced Neuronal Cell Apoptosis
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Jung Nam-Hee
Nam Yu-Hwa
Park Sae-Young
Kim Ji-Yeon
Jung Sung-Chul
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Abstract
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Purpose: Gaucher disease (GD), which is the most prevalent lysosomal storage disorder worldwide, is caused by mutations in the glucocerebrosidase gene (GBA). GD is divided into three clinical subtypes based on the appearance of neurological symptoms. Type 1 GD is a chronic non-neuronopathic disease, and types 2 and 3 are acute neuronopathic and chronic neuronopathic forms, respectively. Neuronopathic GD types 2 and 3 are characterized by increased levels of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph) in the brain, leading to massive loss of neurons.
Methods: DNA damage and subsequent apoptosis of H4 cells were observed following neuroglioma H4 cell culture with GlcCer or GlcSph. Neuronal cell apoptosis was more prominent upon treatment with GlcSph.
Results: When H4 cells were treated with GlcSph in the presence of tubacin, a histone deacetylase 6 inhibitor (HDAC6i), attenuation of both DNA damage and a reduction in the protein expression levels of GlcSph-induced apoptosis-associated factors were observed.
Conclusion: These findings indicated that GlcSph played a prominent role in the pathogenesis of neuronopathic GD by inducing apoptosis, and that HDAC6i could be considered a therapeutic candidate for the treatment of neuronopathic GD.
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KEYWORD
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Glucosylceramide, Glucosylsphingosine, Apoptosis, Gaucher disease, Neuronopathic, Histone deacetylase inhibitor
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