Sirtuin 2, a mammalian homolog of yeast silent information regulator-2 longevity regulator, is an oligodendroglial protein that decelerates cell differentiation through deacetylating alpha-tubulin.

Silent information regulator-2 (SIR2) proteins regulate lifespan of diverse organisms, but their distribution and roles in the CNS remain unclear. Here, we show that sirtuin 2 (SIRT2), a mammalian SIR2 homolog, is an oligodendroglial cytoplasmic protein and localized to the outer and juxtanodal loops in the myelin sheath. Among cytoplasmic proteins of OLN-93 oligodendrocytes, alpha-tubulin was the main substrate of SIRT2 deacetylase. In cultured primary oligodendrocyte precursors (OLPs), SIRT2 emergence accompanied elevated alpha-tubulin acetylation and OLP differentiation into the prematurity stage. Small interfering RNA knockdown of SIRT2 increased the alpha-tubulin acetylation, myelin basic protein expression, and cell arbor complexity of OLPs. SIRT2 overexpression had the opposite effects, and counteracted the cell arborization-promoting effect of overexpressed juxtanodin. SIRT2 mutation concomitantly reduced its deacetylase activity and its impeding effect on OLP arborization. These results demonstrated a counterbalancing role of SIRT2 against a facilitatory effect of tubulin acetylation on oligodendroglial differentiation. Selective SIRT2 availability to oligodendroglia may have important implications for myelinogenesis, myelin-axon interaction, and brain aging.