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The Journal of Neuroscience, January 19, 2005, 25(3):737-747; doi:10.1523/JNEUROSCI.4174-04.2005

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Neurobiology of Disease
Expression of Stathmin, a Developmentally Controlled Cytoskeleton-Regulating Molecule, in Demyelinating Disorders

Aixiao Liu,¹ Christine Stadelmann,² Mario Moscarello,³ Wolfgang Bruck,^2,4 Andre' Sobel,⁵ Fabrizio G. Mastronardi,³ and Patrizia Casaccia-Bonnefil¹

¹Department of Neuroscience, R. Wood Johnson Medical School, Piscataway, New Jersey 08854, ²Department of Neuropathology, University of Goettingen, 13353 Goettingen, Germany, ³Department of Biochemistry, Hospital for Sick Children, Toronto, Ontario, M5G 1X8 Canada, ⁴Hertie Institute of Multiple Sclerosis Research, 13353 Goettingen, Germany, and ⁵Unité 440 Institut National de la Santé et de la Recherche Médical, Institut du Fer a' Moulin Paris, 75005 Paris, France

Understanding the biological relevance of reexpression of developmental molecules in pathological conditions is crucial for the development of new therapies. In this study, we report the increased expression of stathmin, a developmentally regulated tubulin-binding protein, in the brains of patients with multiple sclerosis (MS). In physiological conditions, stathmin immunoreactivity was observed in polysialic acid-neural cell adhesion molecule-positive migratory progenitors in the subventricular zone, and its expression progressively decreased as the cells matured into oligodendrocytes (OLs). In MS patients, however, stathmin levels were elevated in 2',3'-cyclic nucleotide 3'-phosphodiesterase-positive OLs, in 10 of 10 bioptic samples analyzed. Increased levels of stathmin were confirmed by Western blot analysis of normal-appearing white matter samples from MS brains. In addition, using mass spectrometry, stathmin was identified as the main component of a specific myelin protein fraction consistently increased in MS preparations compared with controls.

To test the biological relevance of increased stathmin levels, primary OL progenitors were transfected using a myc-tagged stathmin cDNA and were allowed to differentiate. Consistent with a distinct role played by this molecule in cells of the OL lineage at different developmental stages, transient transfection in progenitors favored the bipolar migratory phenotype but did not affect survival. However, sustained stathmin levels in differentiating OLs, because of overexpression, resulted in enhanced apoptotic susceptibility.

We conclude that stathmin expression in demyelinating disorders could have a dual role. On one hand, by favoring the migratory phenotype of progenitors, it may promote myelin repair. On the other hand, stathmin in mature OLs may indicate cell stress and possibly affect survival.

Key words: multiple sclerosis; myelin; oligodendrocyte; microtubule; repair; demyelination

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Received July 9, 2004; revised November 24, 2004; accepted November 29, 2004.

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