• oligodendrocytes;
  • Sirtuin2;
  • PLP;
  • myelin;
  • development;
  • quaking


Sirtuin 2 (SIRT2), a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase expressed by oligodendrocytes (OLs), the myelin-producing cells of the central nervous system (CNS), is markedly up-regulated during active myelination (Li et al. (2007) J Neurosci 27:2606–2616; Southwood et al. (2007) Neurochem Res 32:187–195; Werner et al. (2007) J Neurosci 27:7717–7730). SIRT2 is a component of the myelin proteome and is severely reduced in the Plp1 knockout mouse brain, in which both proteolipid protein (PLP) and DM20 are absent (Werner et al. (2007) J Neurosci 27:7717–7730). The mechanisms that regulate SIRT2 expression in OLs and myelin remain to be investigated. We report for the first time that the expression of SIRT2 is regulated by the QKI-dependent pathway and this effect is mediated through selective regulation of PLP. In the homozygous quakingviable (qkv/qkv) mutant mouse that harbors QKI deficiency in OLs (Bockbrader and Feng (2008) Future Neurol 3:655–668; Ebersole et al. (1996) Nat Genet 12:260–265; Hardy et al. (1996) J Neurosci 16:7941–7949), PLP, but not DM20 mRNA, was selectively down-regulated and SIRT2 protein was severely reduced whereas SIRT2 mRNA expression was unaffected. Expression of the cytoplasmic isoform QKI6 in OLs (Zhao et al. (2006) J Neurosci 26:11278–11286) rescued SIRT2 expression in the qkv/qkv mutant concomitantly with restoration of PLP expression. Moreover, SIRT2 protein is diminished in myelin tracts and compact myelin of the PLP-ISEdel mutant brain, in which PLP protein but not DM20 is selectively reduced (Wang et al. (2008) Exp Neurol 214:322–330). In contrast, SIRT2 expression and its cellular function in regulating process complexity are not affected by the absence of PLP in PLP-ISEdel non-myelinating OLs. Collectively, our results indicate that the abundance of SIRT2 in myelin is dependent on PLP, but not DM20. © 2011 Wiley Periodicals, Inc.