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

Abstract

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 2Ј,3Ј-cyclic nucleotide 3Ј-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.

Re-Expression of a Developmentally Restricted Potassium Channel in Autoimmune Demyelination

“…The re-expression of developmentally regulated molecules in oligodendroglial cells in demyelinating diseases of the CNS gains increasing attention, as shown for the cytoskeleton regulating molecule stathmin or oligodendroglial Notch signaling. 20,22 Depending on the model investigated, this re-expression of developmentally regulated pathways may have distinct functional implications. 21,49 During myelination and demyelination, Kv1.4 is particularly expressed on oligodendroglial cells.…”

Increased Citrullination of Histone H3 in Multiple Sclerosis Brain and Animal Models of Demyelination: A Role for Tumor Necrosis Factor-Induced Peptidylarginine Deiminase 4 Translocation

“…Immunohistochemistry of Formalin-fixed paraffin-embedded non-neurological control white matter and MS NAWM using anti-citrulline antibody (mAb F95) (Nicholas and Whitaker, 2002;Nicholas et al, 2005) was done according to the methods described previously (Liu et al, 2005;Nicholas et al, 2005). Immunohistochemistry using anti-GFAP, CD3, CD8, and CD68 antibodies for detection of astrocytes, lymphocytes, and activated microglia/macrophages was done with an automated Ventana Medical Systems (Tucson, AZ) Benchmark XT immunostaining system as performed by The Hospital for Sick Children Immunopathology Service laboratory using their standard operating protocols for these reagents.…”

“…Extracts were generated either 1 or 4 d later. Immunofluorescent labeling of Oli-Neu cells was done by the method described by Liu et al (2005). The primary affinity-purified anti-PAD4 rabbit antibody was detected with an anti-rabbit red fluorophore.…”

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

“…This is in agreement with early ultrastructural studies by electron microscopy on the developing corpus callosum of neonatal rats, reporting the progressive increase of chromatin compaction in the nuclei of OPC during their differentiation into mature oligodendrocytes (Kozik 1976). We propose that a critical functional role for massive chromatin compaction is the downregulation of molecules that preclude differentiation, including transcriptional inhibitors of myelin genes (Liu et al 2006;Marin-Husstege et al 2006), as well as cytoskeletal depolymerizing molecules (Liu et al 2003;Liu et al 2005). We further propose that the chromatin compaction initiated by histone deactylation is a critical event to prevent other lineage choice of progenitor cells and possibly prevent precocious myelin gene expression.…”