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Walker et al, 2009;

Guerreiro et al, 2012). SIRT2 is one of the seven known mammalian SIRTs, a family of NAD? -dependent deacetylases. SIRT1 and SIRT6 emerged recently as regulators of several age-related pathologies, in- cluding neurodegenerative diseases and peripheral in?amma- tion (Galli et al, 2011). SIRT2 is expressed as two isoforms, resulting from alternative splicing. The shorter isoform lacks the ?rst

37 amino acids (North et al, 2003), is preferentially expressed in the adult nervous system, and is

20 times more expressed in the hippocampus than other sirtuins (Pandithage et al, 2008). SIRT2 is predominantly cytosolic but the shuttling between the cytoplasm and nucleus explains that both a-tubulin (North et al, 2003) and histones (Vaquero et al, 2006) are deacetylated by this sirtuin. Several studies indicate that SIRT2 plays an important role in brain function. SIRT2 is required for myelination through deacetylation of the polarity protein Par-3, as recently demonstrated by Schwann cell-speci?c ablation of SIRT2 in mice (Beirowski et al, 2011). SIRT2 activity is inhibited by cyclin-dependent kinase-

2 (Cdk2) and Cdk5-dependent phosphorylation at residue S331. Accordingly, the S331A SIRT2 mutant, which cannot be phosphorylated at this speci?c residue, reduces neurite length and tubulin acetylation to a higher extent than the *Corresponding authors. TF Pais, Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Av. Prof. Egas Moniz, Lisboa 1649-028, Portugal. Tel.: ?

351 217999496;

Fax: ?

351 217999412;

E-mail: tfariapais@gmail.com or TF Outeiro, Department of Neurodegeneration........