Reduced sterol regulatory element-binding protein (SREBP) processing through site-1 protease (S1P) inhibition alters oligodendrocyte differentiation in vitro

Hubert Monnerie, Micah Romer, Brigid K. Jensen, John S. Millar, Kelly L. Jordan-Sciutto, Sangwon Kim, Judith B. Grinspan

Research output: Contribution to journalArticle

Abstract

The formation of the myelin membrane of the oligodendrocyte in the CNS is a fundamental process requiring the coordinated synthesis of many different components. The myelin membrane is particularly rich in lipids, however, the regulation of this lipid synthesis is not understood. In other cell types, including Schwann cells, the myelin-forming cells of the PNS, lipid synthesis is tightly regulated by the sterol regulatory element-binding protein (SREBP) family of transcription factors, but this has not been previously shown in oligodendrocytes. We investigated SREBPs’ role during oligodendrocyte differentiation in vitro. Both SREBP-1 and SREBP-2 were expressed in oligodendrocyte precursor cells and differentiating oligodendrocytes. Using the selective site-1 protease (S1P) inhibitor PF-429242, which inhibits the cleavage of SREBP precursor forms into mature forms, we found that preventing SREBP processing inhibited process growth and reduced the expression level of myelin basic protein, a major component of myelin. Further, process extension deficits could be rescued by the addition of exogenous cholesterol. Blocking SREBP processing reduced mRNA transcription and protein levels of SREBP target genes involved in both the fatty acid and the cholesterol synthetic pathways. Furthermore, de novo levels and total levels of cholesterol synthesis were greatly diminished when SREBP processing was inhibited. Together these results indicate that SREBPs are important regulators of oligodendrocyte maturation and that perturbation of their activity may affect myelin formation and integrity. (Figure presented.). Cover Image for this issue: doi: 10.1111/jnc.13781.

Original languageEnglish (US)
Pages (from-to)53-67
Number of pages15
JournalJournal of Neurochemistry
Volume140
Issue number1
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

Fingerprint

Sterol Regulatory Element Binding Proteins
Oligodendroglia
Myelin Sheath
Processing
Cholesterol
Lipids
Sterol Regulatory Element Binding Protein 2
Sterol Regulatory Element Binding Protein 1
Membranes
Protein Precursors
Myelin Basic Protein
Schwann Cells
Transcription
Protease Inhibitors
site 1 membrane-bound transcription factor peptidase
Transcription Factors
Fatty Acids
Genes
Cells
Messenger RNA

Keywords

  • lipid
  • myelin
  • oligodendrocyte
  • process growth
  • SREBP

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Reduced sterol regulatory element-binding protein (SREBP) processing through site-1 protease (S1P) inhibition alters oligodendrocyte differentiation in vitro. / Monnerie, Hubert; Romer, Micah; Jensen, Brigid K.; Millar, John S.; Jordan-Sciutto, Kelly L.; Kim, Sangwon; Grinspan, Judith B.

In: Journal of Neurochemistry, Vol. 140, No. 1, 01.01.2017, p. 53-67.

Research output: Contribution to journalArticle

Monnerie, Hubert ; Romer, Micah ; Jensen, Brigid K. ; Millar, John S. ; Jordan-Sciutto, Kelly L. ; Kim, Sangwon ; Grinspan, Judith B. / Reduced sterol regulatory element-binding protein (SREBP) processing through site-1 protease (S1P) inhibition alters oligodendrocyte differentiation in vitro. In: Journal of Neurochemistry. 2017 ; Vol. 140, No. 1. pp. 53-67.
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