• The Korean Journal of Physiology and Pharmacology
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• v.27 no.1
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• pp.21-29
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• 2023

The poor outcome of advanced ovarian cancer under conventional therapy necessitates new strategies to improve therapeutic efficacy. β-glucosidase (encoded by GBA) is a lysosomal enzyme and is involved in sphingolipids metabolism. Recent studies revealed that β-glucosidase plays a role in cancer development and chemoresistance. In this work, we systematically evaluated the expression and role of GBA in ovarian cancer. Our work demonstrates that inhibition of β-glucosidase has therapeutic potential for ovarian cancer. Gene Expression Profiling Interactive Analysis database, western blot and immunohistochemistry analyses of patient samples demonstrated that GBA mRNA and protein expression levels were significantly increased in ovarian cancer compared to normal tissues. Functional studies using gainof-function and loss-of-function approaches demonstrated that GBA overexpression did not affect growth and migration but alleviated cisplatin's efficacy in ovarian cancer cells. In addition, GBA depletion resulted in growth inhibition, apoptosis induction, and enhancement of cisplatin's efficacy. Of note, we found that GBA inhibition specifically decreased receptor tyrosine kinase AXL level, leading to the suppression of AXL-mediated signaling pathways. Our data suggest that GBA represents a promising target to inhibit AXL signaling and overcome cisplatin resistance in ovarian cancer.

• Molecules and Cells
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• v.38 no.9
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• pp.806-813
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• 2015

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the glucocerebrosidase gene (GBA), which encodes the lysosomal enzyme glucosylceramidase (GCase). Deficiency in GCase leads to characteristic visceral pathology and lethal neurological manifestations in some patients. Investigations into neurogenesis have suggested that neurodegenerative disorders, such as GD, could be overcome or at least ameliorated by the generation of new neurons. Bone marrowderived mesenchymal stem cells (BM-MSCs) are potential candidates for use in the treatment of neurodegenerative disorders because of their ability to promote neurogenesis. Our objective was to examine the mechanism of neurogenesis by BM-MSCs in GD. We found that neural stem cells (NSCs) derived from a neuronopathic GD model exhibited decreased ability for self-renewal and neuronal differentiation. Co-culture of GBA-deficient NSCs with BM-MSCs resulted in an enhanced capacity for self-renewal, and an increased ability for differentiation into neurons or oligodendrocytes. Enhanced proliferation and neuronal differentiation of GBA-deficient NSCs was associated with elevated release of macrophage colony-stimulating factor (M-CSF) from BM-MSCs. Our findings suggest that soluble M-CSF derived from BM-MSCs can modulate GBA-deficient NSCs, resulting in their improved proliferation and neuronal differentiation.

• Clinical and Experimental Pediatrics
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• v.55 no.2
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• pp.48-53
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• 2012

Purpose: Gaucher disease is caused by a ${\beta}$-glucocerebrosidase (GBA) deficiency. The aim of this study is to investigate the clinical and genetic characteristics according to subtypes of Gaucher disease in the Korean population. Methods: Clinical findings at diagnosis, $GBA$ mutations, and clinical courses were reviewed in 20 patients diagnosed with Gaucher disease. Results: Eleven patients were diagnosed with non-neuronopathic type, 2 with acute neuronopathic type, and 7 with chronic neuronopathic type. Most patients presented with hepatosplenomegaly, thrombocytopenia, and short stature. In the neuronopathic group, variable neurological features, such as seizure, tremor, gaze palsy, and hypotonia, were noted at age $8.7{\pm}4.3$ years. B cell lymphoma, protein-losing enteropathy, and hydrops fetalis were the atypical manifestations. Biomarkers, including chitotriosidase, acid phosphatase, and angiotensin-converting enzyme, increased at the initial evaluation and subsequently decreased with enzyme replacement treatment (ERT). The clinical findings, including hepatosplenomegaly, thrombocytopenia, and skeletal findings, improved following ERT, except for the neurological manifestations. L444P was the most common mutation in our cohort. One novel mutation, R277C, was found. Conclusion: Although the clinical outcome for Gaucher disease improved remarkably following ERT, the outcome differed according to subtype. Considering the high proportion of the neuronopathic form in the Korean population, new therapeutic strategies targeting the central nervous system are needed, with the development of a new scoring system and biomarkers representing clinical courses in a more comprehensive manner.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.17 no.2
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• pp.63-68
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• 2017

Gaucher disease (GD) is caused by the deficiency of glucocerebrosidase. In pediatric patients with GD, especially Type I GD, enzyme replacement therapy (ERT) can reduce the hepatosplenomegaly and improve the hematologic finding and growth velocity. Herein, we report a 2-year-old girl with Type I GD presented with hepatosplenomegaly, bone pain and growth retardation. A 2 year-old-girl was referred to our hospital due to severe hepatosplenomegaly and growth retardation. She suffered from both leg pain and chronic fatigue. Simple x-ray showed widened distal long bones like that of an 'Erlenmeyer flask' which is associated with GD. The laboratory test showed anemia and thrombocytopenia. The enzyme activity was markedly reduced and the direct sequencing of the GBA gene showed the compound heterozygous mutations, p.G46E and p.L444P. As the G46E have been considered as the protective gene against neuronopathic genotype, we could assess the Type I GD in this patient. After one year of ERT, the growth velocity became 11 cm per year. Bone pain and fatigue disappeared. The volume of liver and spleen was reduced from $683cm^3$ and $703cm^3$ to $590cm^3$ and $235cm^3$, respectively. Although GD is an extremely rare disease in Korea, growth retardation and bone pain in children are the important signs which lead to early detection of GD and a simple radiologic finding is helpful to assess the GD at outpatient clinic. We highlight that the early diagnosis and early ERT is important for good growth and outcome for pediatric patients with GD.

• Journal of Animal Science and Technology
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• v.62 no.3
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• pp.293-305
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• 2020

The difference in the breeding programs and population history may have diversely shaped the genomes of Korean native cattle breeds. In the absence of phenotypic data, comparisons of breeds that have been subjected to different selective pressures can aid to identify genomic regions and genes controlling qualitative and complex traits. In this study to decipher genetic variation and identify evidence of divergent selection, 3 Korean cattle breeds were genotyped using the recently developed high-density GeneSeek Genomic Profiler F250 (GGP-F250) array. The three Korean cattle breeds clustered according to their coat color phenotypes and breeding programs. The Heugu breed reliably showed smaller effective population size at all generations considered. Across the autosomal chromosomes, 113 and 83 annotated genes were identified from Hanwoo-Chikso and Hanwoo-Heugu comparisons, respectively of which 16 genes were shared between the two pairwise comparisons. The most important signals of selection were detected on bovine chromosomes 14 (24.39-25.13 Mb) and 18 (13.34-15.07 Mb), containing genes related to body size, and coat color (XKR4, LYN, PLAG1, SDR16C5, TMEM68, CDH15, MC1R, and GALNS). Some of the candidate genes are also associated with meat quality traits (ACSF3, EIF2B1, BANP, APCDD1, and GALM) and harbor quantitative trait locus (QTL) for beef production traits. Further functional analysis revealed that the candidate genes (DBI, ACSF3, HINT2, GBA2, AGPAT5, SCAP, ELP6, APOB, and RBL1) were involved in gene ontology (GO) terms relevant to meat quality including fatty acid oxidation, biosynthesis, and lipid storage. Candidate genes previously known to affect beef production and quality traits could be used in the beef cattle selection strategies.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.20 no.1
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• pp.1-13
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• 2020

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.