Scholarlink

<p>Gaucher disease arises from mutations in glucocerebrosidase resulting in accumulation of glucosylceramide, which is deacylated to glucosylsphingosine. Mutations in glucocerebrosidase are the greatest known genetic risk factor for Parkinson’s disease. Glucosylsphingosine is a biomarker for Gaucher disease and studies demonstrate its relevance to disease pathology, yet the mechanisms of its toxicity remain little understood. Using proteomics, we show that incubation of SH-Sy5y cells with glucosylsphingosine at physiological plasma concentrations observed in moderate/ severe Gaucher disease negatively effects the TCA cycle, mitochondrial function, glycolysis and protein ubiquitination. Functional analyses confirmed that glucosylsphingosine reduces ATP production, elicits oxidative stress and an increase of glycolysis. Analyses of ubiquitinated proteins and lipid-binding studies demonstrated that glucosylsphingosine has binding affinity for tubulin alpha and induced a specific increase of ubiquitination of α and β tubulins. In conclusion, supranormal levels of glucosylsphingosine affect cellular energy metabolism which may contribute to the pathology in Gaucher disease.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Glucosylsphingosine affects mitochondrial function in a neuronal cell model

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月21日

查看全文
  • Valeria Nikolaenko,
  • Reddy Vootukuri,
  • Simon Eaton,
  • Jenny Hällqvist,
  • Tomas Baldwin,
  • Kevin Mills,
  • Wendy Heywood

摘要

Gaucher disease arises from mutations in glucocerebrosidase resulting in accumulation of glucosylceramide, which is deacylated to glucosylsphingosine. Mutations in glucocerebrosidase are the greatest known genetic risk factor for Parkinson’s disease. Glucosylsphingosine is a biomarker for Gaucher disease and studies demonstrate its relevance to disease pathology, yet the mechanisms of its toxicity remain little understood. Using proteomics, we show that incubation of SH-Sy5y cells with glucosylsphingosine at physiological plasma concentrations observed in moderate/ severe Gaucher disease negatively effects the TCA cycle, mitochondrial function, glycolysis and protein ubiquitination. Functional analyses confirmed that glucosylsphingosine reduces ATP production, elicits oxidative stress and an increase of glycolysis. Analyses of ubiquitinated proteins and lipid-binding studies demonstrated that glucosylsphingosine has binding affinity for tubulin alpha and induced a specific increase of ubiquitination of α and β tubulins. In conclusion, supranormal levels of glucosylsphingosine affect cellular energy metabolism which may contribute to the pathology in Gaucher disease.