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Inhibitory Action of a Histone Deacetylase 6 Inhibitor on Glucosylceramide- and Glucosylsphingosine-induced Neuronal Cell Apoptosis  

Jung, Namhee (Department of Biochemistry, College of Medicine, Ewha Womans University)
Nam, Yu Hwa (Department of Biochemistry, College of Medicine, Ewha Womans University)
Park, Saeyoung (Department of Biochemistry, College of Medicine, Ewha Womans University)
Kim, Ji Yeon (Department of Biochemistry, College of Medicine, Ewha Womans University)
Jung, Sung-Chul (Department of Biochemistry, College of Medicine, Ewha Womans University)
Publication Information
Journal of The Korean Society of Inherited Metabolic disease / v.20, no.1, 2020 , pp. 1-13 More about this Journal
Abstract
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.
Keywords
Glucosylceramide; Glucosylsphingosine; Apoptosis; Gaucher disease; Neuronopathic; Histone deacetylase inhibitor;
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