Novel molecular insights into the critical role of sulfatide in myelin maintenance/function

Juan Pablo Palavicini, Chunyan Wang, Linyuan Chen, Sareen Ahmar, Juan Diego Higuera, Jeffrey L. Dupree, Xianlin Han

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Cerebroside sulfotransferase (CST) catalyzes the production of sulfatide, a major class of myelin-specific lipids. CST knockout (CST−/−) mice in which sulfatide is completely depleted are born healthy, but display myelin abnormalities and progressive tremors starting at 4–6 weeks of age. Although these phenotypes suggest that sulfatide plays a critical role in myelin maintenance/function, the underlying mechanisms remain largely unknown. We analyzed the major CNS myelin proteins and the major lipids enriched in the myelin in a spatiotemporal manner. We found a one-third reduction of the major compact myelin proteins (myelin basic protein, myelin basic protein, and proteolipid protein, PLP) and an equivalent post-developmental loss of myelin lipids, providing the molecular basis behind the thinner myelin sheaths. Our lipidomics data demonstrated that the observed global reduction of myelin lipid content was not because of an increase of lipid degradation but rather to the reduction of their synthesis by oligodendrocytes. We also showed that sulfatide depletion leads to region-specific effects on non-compact myelin, dramatically affecting the paranode (neurofascin 155) and the major inner tongue myelin protein (myelin-associated glycoprotein). Moreover, we demonstrated that sulfatide promotes the interaction between adjacent PLP extracellular domains, evidenced by a progressive decline of high molecular weight PLP complexes in CST−/− mice, providing an explanation at a molecular level regarding the uncompacted myelin sheaths. Finally, we proposed that the dramatic losses of neurofascin 155 and PLP interactions are responsible for the progressive tremors and eventual ataxia. In summary, we unraveled novel molecular insights into the critical role of sulfatide in myelin maintenance/function. (Figure presented.) Cerebroside sulfotransferase (CST) catalyzes the production of sulfatide, a major class of myelin-specific lipids. CST knockout (CST−/−) mice in which sulfatide is completely depleted are born healthy, but display myelin abnormalities We show in our study that sulfatide depletion leads to losses of myelin proteins and lipids, and impairment of myelin functions, unraveling novel molecular insights into the critical role of sulfatide in myelin maintenance/function.

Original languageEnglish (US)
Pages (from-to)40-54
Number of pages15
JournalJournal of neurochemistry
Volume139
Issue number1
DOIs
StatePublished - Oct 1 2016
Externally publishedYes

Keywords

  • cerebroside sulfotransferase
  • myelin lipidome
  • myelin-associated glycoprotein
  • proteolipid protein
  • shotgun lipidomics
  • sulfatide

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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