Endosomes and lysosomes play distinct roles in sulfatide-induced neuroblastoma apoptosis: Potential mechanisms contributing to abnormal sulfatide metabolism in related neuronal diseases

Youchun Zeng, Hua Cheng, Xuntian Jiang, Xianlin Han

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Alterations in sulfatide metabolism, trafficking and homoeostasis are present at the earliest clinically recognizable stages of Alzheimer's disease and are associated with metachromatic leukodystrophy. However, the role of sulfatide in these disease states remains unknown. In the present study, we investigated the sequelae of NB (neuroblastoma) cells upon sulfatide supplementation and the biochemical mechanisms contributing to the sulfatide-induced changes. By using shotgun lipidomics, we showed dramatic accumulations of sulfatide, ceramide and sphingosine in NB cells in a time- and dose-dependent manner. Further studies utilizing subcellular fractionation and shotgun lipidomics analyses demonstrated that most of the increased ceramide content was generated in the endosomal compartment, whereas sulfatides predominantly accumulated in lysosomes. In addition, we determined that the sulfatide-mediated increase in endosomal ceramide content mainly resulted from β-galactosidase activity, which directly hydrolyses sulfatide to ceramide without a prior desulfation step. Substantial cell apoptosis occurred in parallel with the accumulation of sulfatides and ceramides, as revealed by mitochondrial membrane depolarization, by phosphatidylserine translocation and by the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) assay. These findings were also demonstrated with primary neuron cultures. Collectively, our results demonstrate that abnormal sulfatide metabolism can induce cell apoptosis due to endosome-mediated ceramide generation and the accumulation of cytotoxic levels of sulfatides in lysosomes.

Original languageEnglish (US)
Pages (from-to)81-92
Number of pages12
JournalBiochemical Journal
Volume410
Issue number1
DOIs
StatePublished - Feb 15 2008
Externally publishedYes

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Keywords

  • Alzheimer's disease (AD)
  • Ceramide
  • Electrospray ionization MS (ESI-MS)
  • Metachromatic leukodystrophy
  • Shotgun lipidomics
  • Sulfatide

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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