title: The QKI-PLP pathway controls SIRT2 abundance in CNS myelin.
abstract: 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 (qk(v) /qk(v) ) 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 qk(v) /qk(v) 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.
authors.affiliation: Department of Neurology, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhu
authors.forename: L
authors.initials: L
authors.lastname: Zhao
authors.forename: E
authors.initials: E
authors.lastname: Wang
authors.forename: N
authors.initials: N
authors.lastname: Dimova
authors.forename: G
authors.initials: G
authors.lastname: Liu
authors.forename: Y
authors.initials: Y
authors.lastname: Feng
authors.forename: F
authors.initials: F
authors.lastname: Cambi
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology*; D002454:Cell Differentiation; D005434:Flow Cytometry; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008821:Mice, Quaking; D008822:Mice, Transgenic; D009154:Mutation; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000378:metabolism*; D009186:Myelin Sheath / Q000378:metabolism*; D009836:Oligodendroglia / Q000378:metabolism*; D012333:RNA, Messenger; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D056565:Sirtuin 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D018991:Myelin Proteolipid Protein; C047516:Plp1 protein, mouse; C098217:Qk protein, mouse; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C418743:Sirt2 protein, mouse; D056565:Sirtuin 2; D017461:Receptors, Atrial Natriuretic Factor; C073616:atrial natriuretic factor receptor C