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Reduced sterol regulatory element‐binding protein ( SREBP ) processing through site‐1 protease (S1P) inhibition alters oligodendrocyte differentiation in vitro
Author(s) -
Monnerie Hubert,
Romer Micah,
Jensen Brigid K.,
Millar John S.,
JordanSciutto Kelly L.,
Kim Sangwon F.,
Grinspan Judith B.
Publication year - 2017
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13721
Subject(s) - sterol regulatory element binding protein , oligodendrocyte , myelin , microbiology and biotechnology , biology , biochemistry , transcription factor , sterol , myelin basic protein , chemistry , cholesterol , endocrinology , central nervous system , gene
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 SREBP s' 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 SREBP s are important regulators of oligodendrocyte maturation and that perturbation of their activity may affect myelin formation and integrity.Cover Image for this issue: doi: 10.1111/jnc.13781 .