Role of myelin-associated NAD+- dependent deacetylase Sirtuin 2 in modifying axonal degeneration

Abstract

-In the central nervous system (CNS), oligodendrocytes (OLs) ensheath axons with lipid-rich myelin membranes that provide an electrical insulation and are essential for fast nerve impulse transmission. However, myelination is not the only function of OLs, which is important for neurons. The axo-glial interaction is vital for the long-term survival of the axons, independently from myelination. The novel role of OLs in supporting axonal integrity was best exemplified by the findings on mutant mice with the genetic deletion of two structural proteins of the CNS myelin, namely proteolipid protein (PLP) and 2'-3'-cyclic nucleotide phosphodiesterase (CNP1). Lack of these proteins led to an axonopathy in the CNS, despite the absence of major myelin abnormalities. Gel-based proteome analysis performed to explore possible secondary molecular alterations in Plp null myelin revealed that Sirtuin 2 (SIRT2) was the only protein, other than PLP and its splice isoform DM20, to be virtually absent. These findings suggested that the axonal pathology observed in Plp null mice may be at least partially due to the lack of SIRT2.SIRT2 is one of the mammalian orthologs of the silent information regulator 2 (Sir2) protein, which is an nicotinamide adenine dinucleotide (NAD + )-dependent histone deacetylase and is involved in many cellular mechanisms in yeast and worms. SIRT2 has a cytoplasmic distribution, to colocalize with microtubule network and to deacetylate α-tubulin at the lysine-40 residue. SIRT2 is highly expressed in the brain, specifically in oligodendrocytes at early stages of myelination and is incorporated into myelin in presence of PLP/DM20, being localized at the inner and outer loops and the paranodes of the CNS myelin.To identify the role of SIRT2 in the axon protection, we analyzed mice lacking Sirt2 expression. Surprisingly, we found that SIRT2 is dispensable for myelin formation and maintenance, as axons of all calibers in both the central and peripheral nervous system were normally myelinated in the Sirt2 null mice. In addition, these mice showed no apparent CNS axonopathy suggesting that SIRT2 may not be the only key player of the yet unexplained axonoprotective function of PLP.To test the hypothesis that SIRT2 serves as an NAD + -dependent regulator of glial neuroprotection, we did not only use pharmacological approaches to induce axonal stress, but we also generated double mutant mice expressing neuronal and glial disease genes. For example, we found that the axonal degeneration caused by the lack of Cnp1 was dramatically enhanced by the additional absence of Sirt2. As a result, the Sirt2*Cnp1 double null mutant mice displayed increased inflammation, and a significantly reduced lifespan. These findings support the hypothesis that SIRT2 is a myelin-associated sensor for axonal stress that is essential for long-term axonal survival. the cytoplasm of OLs. The compaction of the opposing outer leaflets form the intraperiod lines (IPL), which are interseparating the MDL (courtesy to Dr. Wiebke Möbius, EM Facility, Ma...