Does Sirt2 Regulate Cholesterol Biosynthesis DuringOligodendroglial Differentiation In Vitro and In Vivo?

Abstract Sirtuin2 (SIRT2) is a deacetylase enzyme predominantlyexpressed in myelinating glia of the centralnervous system (CNS). We have previously demonstratedthat Sirt2 expression enhances oligodendrocyte (OL) differentiationand arborization in vitro, but the moleculartargets of SIRT2 in OLs remain speculative. SIRT2 hasbeen implicated in cholesterol biosynthesis by promotingthe nuclear translocation of sterol regulatory elementbinding protein (SREBP)-2. We investigated this further inCNS myelination by examining the role of Sirt2 incholesterol biosynthesis in vivo and in vitro employingSirt2-/- mice, primary OL cells and CG4-OL cells. Ourresults demonstrate that expression of cholesterol biosyntheticgenes in the CNS white matter or cholesterol contentin purified myelin fractions did not differ between Sirt2-/-and age-matched wild-type mice. Cholesterol biosyntheticgene expression profiles and total cholesterol content werenot altered in primary OLs from Sirt2-/- mice and in CG4-OLs when Sirt2 was either down-regulated with RNAi oroverexpressed. In addition, Sirt2 knockdown or overexpressionin CG4-OLs had no effect on SREBP-2 nucleartranslocation. Our results indicate that Sirt2 does notimpact the expression of genes encoding enzymes involvedin cholesterol biosynthesis, total cholesterol content, ornuclear translocation of SREBP-2 during OL differentiationand myelination.Keywords Oligodendrocyte Myelin SIRT2 SREBP-2 Cholestero