It has been shown that Wallerian degeneration, an anterograde degeneration of 
transected axons, is markedly delayed in a mutant mouse called slow Wallerian 
degeneration (Wld(S)). These mice also show resistance to axonal degeneration 
caused by microtubule depolymerizing drugs, suggesting that axonal microtubules 
are stabilized. Here, we have focused on tubulin acetylation, a 
post-translational modification associated with microtubule stability. We found 
that the basal level of microtubule acetylation was increased in cultured 
cerebellar granule cells from Wld(S) mice. Nicotinamide but not 
3-aminobenzamide, an inhibitor for poly(ADP)ribose polymerase, enhanced tubulin 
acetylation and resistance to axonal degeneration in cultured cerebellar granule 
cells from wild-type (WT) mice, suggesting that mammalian Sir2-related protein 
(SIRT) 2, a nicotinamide adenine dinucleotide (NAD)--dependent tubulin 
deacetylase, could modulate resistance to axonal degeneration. Indeed, the 
levels of NAD and SIRT2 were decreased in the cytoplasm from Wld(S) granule 
cells. Moreover, SIRT2 overexpression abrogated microtubule hyperacetylation and 
resistance to axonal degeneration in these cells. Conversely, SIRT2 knockdown by 
using a lentiviral vector expressing small interfering RNA, enhanced microtubule 
acetylation and resistance to axonal degeneration in WT granule cells. Taken 
together, these results suggest that SIRT2-mediated tubulin deacetylation is 
involved in both microtubule hyperacetylation and resistance to axonal 
degeneration in Wld(S) granule cells.