대한유전성대사질환학회지 (Journal of The Korean Society of Inherited Metabolic disease)

대한유전성대사질환학회 (The Korea Society of Inherited Metabolic Disease)
권호 표지

Glucosylceramide와 glucosylsphingosine에 의해 유도되는 신경세포 사멸에 대한 HDAC 저해제의 억제 효과 연구

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

  • 정남희 (이화여자대학교 의과대학 생화학교실) ;
  • 남유화 (이화여자대학교 의과대학 생화학교실) ;
  • 박세영 (이화여자대학교 의과대학 생화학교실) ;
  • 김지연 (이화여자대학교 의과대학 생화학교실) ;
  • 정성철 (이화여자대학교 의과대학 생화학교실)
  • 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)
  • 발행 : 2020.06.30
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초록

Gaucher disease (GD)는 glucocerebrosidase 유전자(GBA)의 돌연변이에 의하여 발병하는 전세계적으로 가장 유병율이 높은 리소좀 축적질환이다. GD는 신경학적인 증상의 유무에 따라 3가지 임상형으로 구분된다. 신경병증 GD인 2형과 3형의 경우는 대뇌에서 glucosylceramide (GlcCer)와 glucosylsphingosine (GlcSph)의 농도가 증가하면서 신경세포의 심각한 손실이 야기되는 특징을 보인다. 신경교종에서 유래한 H4 세포를 GD에서 증가하는 기질인 GluCer와 GlcSph를 첨가하여 배양하였을 때, 심각한 DNA손상과 더불어 세포의 사멸이 야기되는 것과 이러한 신경세포의 사멸은 GluCer 보다는 GlcSph을 처리하였을 때 더 현저하게 증가하는 것을 관찰하였다. H4 세포에 히스톤 탈아세틸화 효소(HDAC) 6의 저해제인 tubacin과 GlcSph을 함께 처리하였을 경우에는 DNA손상은 물론 GlcSph에 의하여 유도된 세포사멸과 관련된 단백질 인자들의 발현이 모두 감소되었다. 본 연구를 통해 GlcSph이 세포사멸을 통하여 신경병증 GD의 발병에 주요한 역할을 한다는 것을 알 수 있었고, HDAC6 저해제가 신경병증 GD 환자를 위한 치료제 후보물질로 제시될 수 있는 가능성을 확인하였다.

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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