H. Zhu, L. Zhao, and E. Wang contributed equally to this work.
The QKI-PLP pathway controls SIRT2 abundance in CNS myelin
Article first published online: 21 SEP 2011
Copyright © 2011 Wiley Periodicals, Inc.
Volume 60, Issue 1, pages 69–82, January 2012
How to Cite
Zhu, H., Zhao, L., Wang, E., Dimova, N., Liu, G., Feng, Y. and Cambi, F. (2012), The QKI-PLP pathway controls SIRT2 abundance in CNS myelin. Glia, 60: 69–82. doi: 10.1002/glia.21248
- Issue published online: 14 NOV 2011
- Article first published online: 21 SEP 2011
- Manuscript Accepted: 30 AUG 2011
- Manuscript Received: 7 APR 2011
- NIH/NINDS. Grant Number: RO1NS053905
- European Leukodystrophy Association. Grant Number: 2008-013I1
- NIH/NINDS. Grant Number: R01NS056097
- NMSS. Grant Number: RG4010-A-2
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.