Proteolipid Protein Is Required for Transport of Sirtuin 2 into CNS Myelin

Abstract

Mice lacking the expression of proteolipid protein (PLP)/DM20 in oligodendrocytes provide a genuine model for spastic paraplegia (SPG-2). Their axons are well myelinated but exhibit impaired axonal transport and progressive degeneration, which is difficult to attribute to the absence of a single myelin protein. We hypothesized that secondary molecular changes in PLP null myelin contribute to the loss of PLP/DM20-dependent neuroprotection and provide more insight into glia-axonal interactions in this disease model. By gel-based proteome analysis, we identified Ͼ160 proteins in purified myelin membranes, which allowed us to systematically monitor the CNS myelin proteome of adult PLP null mice, before the onset of disease. We identified three proteins of the septin family to be reduced in abundance, but the nicotinamide adenine dinucleotide (NAD ϩ )-dependent deacetylase sirtuin 2 (SIRT2) was virtually absent. SIRT2 is expressed throughout the oligodendrocyte lineage, and immunoelectron microscopy revealed its association with myelin. Loss of SIRT2 in PLP null was posttranscriptional, suggesting that PLP/DM20 is required for its transport into the myelin compartment. Because normal SIRT2 activity is controlled by the NAD ϩ /NADH ratio, its function may be coupled to the axo-glial metabolism and the long-term support of axons by oligodendrocytes.

Myelin matters: proteomic insights into white matter disorders

“…1). Nevertheless, by implementing different technical adjustments, various gel-based and shotgun-type proteomic approaches have been applied to myelin purified from rodent brains [24][25][26][27] and subfractions yielded by sucrose-density gradient centrifugation ('axogliasomes' [28]) or chromatographic separation [29]. Such analyses have proven very robust across different laboratories (see [30] for a comprehensive review on myelin proteome analysis).…”

Post-Translational Modifications of Nucleosomal Histones in Oligodendrocyte Lineage Cells in Development and Disease

“…Recent reports have uncovered an intriguing association between SIRT2 levels and the myelin protein PLP (Werner et al 2007). It was discovered that the incorporation of SIRT2 into the myelin sheath is myelin protein PLP/DM20-dependent; as in the plp null mice, SIRT2 expression is completely lost (Werner et al 2007).…”

“…It was discovered that the incorporation of SIRT2 into the myelin sheath is myelin protein PLP/DM20-dependent; as in the plp null mice, SIRT2 expression is completely lost (Werner et al 2007). …”

“…This memory is responsible for the downregulation and stable repression of inhibitory molecules in differentiated oligodendrocytes . In an attempt to understand the potential mechanisms underlying age-dependent decline of repair function, Shen et al (2007) reported the progressive loss of this "epigenetic memory" in oligodendrocytes during normal aging. Decreased histone deacetylation and repressive methylation of histone H3 tails were detected in older mice.…”

“…Decreased histone deacetylation and repressive methylation of histone H3 tails were detected in older mice. The direct result of these epigenetic changes was the increased expression of inhibitory molecules, including Hes5, Ids, and Sox2 (Shen et al 2007). This partially explains why the responsiveness of oligodendrocytes to extracellular factors is decreased with aging and further suggests that chromatin modifications and changes in the "epigenetic memory" of oligodendrocytes may have profound effects on therapeutic outcomes.…”