The QKI‐PLP pathway controls SIRT2 abundance in CNS myelin

Abstract

Sirtuin 2 (SIRT2), a 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; Southwood et al. 2007; Werner et al. 2007). SIRT2 is a component of the myelin proteome and is severely reduced in the Plp1 knockout mouse brain, in which both PLP and DM20 are absent (Werner et al. 2007). 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; Ebersole et al. 1996; Hardy et al. 1996), PLP, but not DM20 mRNA, was selectively down-regulated and SIRT2 protein was severely reduced while SIRT2 mRNA expression was unaffected. Expression of the cytoplasmic isoform QKI6 in OLs (Zhao et al. 2006) 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). 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 oligodendrocytes. Collectively, our results indicate that the abundance of SIRT2 in myelin is dependent on PLP, but not DM20.

NAD Biosynthesis in Humans - Enzymes, Metabolites and Therapeutic Aspects

“…In paper I, analysis of cDNA from several human cell lines revealed the existence of a new splice variant and confirmed the previously reported data from mice [143,144].…”

“…All sirtuins share a highly conserved catalytic domain, consisting of approximately 275 amino acids, but vary with regard to the lengths of their N-and C-terminal parts [24,28]. The 3D structure of the catalytic domain is highly similar for all sirtuins, including SIRT2, the sirtuin of interest in this study ( Figure 4A).…”

“…Seven homologs to Sir2p, named sirtuins (SIRTs), have been identified in mammals (SIRT1-7) [24,25]. Expressed ubiquitously in all tissues, they vary in their subcellular location and activity (Table 1).…”

“…Since deletion of the NES led to nucleocytoplasmic distribution, it was suggested to mediate their cytosolic localization [21]. Cytosolic functions of SIRT2 include the regulation of microtubule acetylation, control of myelination in the central and peripheral nervous system and gluconeogenesis [15,[22][23][24]. There is growing evidence for additional functions of SIRT2 in the nucleus.…”

“…This raises the question as to how the nuclear presence of SIRT2 is brought about. In mice, another Sirt2 splice variant was demonstrated [24,30]. Interestingly, the corresponding protein would lack the amino acids that constitute the NES in the human isoforms.…”