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The Journal of Neuroscience, July 18, 2007, 27(29):7717-7730; doi:10.1523/JNEUROSCI.1254-07.2007

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Development/Plasticity/Repair
Proteolipid Protein Is Required for Transport of Sirtuin 2 into CNS Myelin

Hauke B. Werner,^1 * Katja Kuhlmann,^1,4 * Siming Shen,³ Marina Uecker,^2,4 Anke Schardt,¹ Kalina Dimova,² Foteini Orfaniotou,¹ Ajit Dhaunchak,¹ Bastian G. Brinkmann,¹ Wiebke Möbius,¹ Lenny Guarente,⁵ Patrizia Casaccia-Bonnefil,³ Olaf Jahn,^2,4 and Klaus-Armin Nave^1,4

¹Department of Neurogenetics and ²Proteomics Group, Max Planck Institute of Experimental Medicine, D-37075 Goettingen, Germany, ³Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, ⁴Deutsche Forschungsgemeinschaft Research Center for Molecular Physiology of the Brain, 37073 Goettingen, Germany, and ⁵Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

Correspondence should be addressed to either Dr. Hauke Werner or Dr. Klaus-Armin Nave, Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Hermann-Rein-Strasse 3, D-37075 Goettingen, Germany, Email: hauke{at}em.mpg.de or Email: nave{at}em.mpg.de

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 >160 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⁺)-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⁺/NADH ratio, its function may be coupled to the axo-glial metabolism and the long-term support of axons by oligodendrocytes.

Key words: myelin; oligodendrocyte; cytoskeleton; neurodegeneration; Pelizaeus–Merzbacher disease; hereditary spastic paraplegia; NAD⁺/NADH; acetylation; metabolism

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Received March 20, 2007; revised April 30, 2007; accepted June 4, 2007.

Correspondence should be addressed to either Dr. Hauke Werner or Dr. Klaus-Armin Nave, Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Hermann-Rein-Strasse 3, D-37075 Goettingen, Germany, Email: hauke{at}em.mpg.de or Email: nave{at}em.mpg.de

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