Sirtuin2 in the CNS: Expression, functional roles, action mechanism and mutation-induced alteration of molecular /cell biological properties

Abstract

Silent information regulator-2 proteins regulate lifespan of diverse organisms, but their roles in the nervous system were largely unknown. The current study focused on expression, functions and clinical relevance of sirtuin2 in the central nervous system. We found specific SIRT2 expression in oligodendroglia, and enriched SIRT2 distribution in the outer and juxtanodal terminal loops of myelin sheath. Further experiments revealed an inhibitory function of SIRT2 on oligodendroglial differentiation via SIRT2 deacetylation of alpha-tubulin. Overexpression of specific rat SIRT2 mutants induced formation of cytoplasmic aggregates, the propensities of which were inversely correlated to the solubility of mutated SIRT2. A unique 37-residue N-terminal domain of human SIRT2 (hNter) protected SIRT2 mutants from solubility loss and aggregation. Our data calls for further investigations to test the essence of SIRT2 for Myelination, myelin-axon interaction and brain aging, as well as of SIRT2 mutations or polymorphisms for neurodegenerative diseases.