Paclitaxel (Taxol) attenuates clinical disease in a spontaneously                 demyelinating transgenic mouse and induces remyelination

Moscarello, Mario A.; Mak, Baldwin; Nguyen, Tao; Wood, D. D.; Mastronardi, Fabrizio G.; Ludwin, Samuel K.

doi:10.1191/1352458502ms776oa

Cited by 40 publications

(43 citation statements)

References 49 publications

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“…Together, these data suggest that upregulation of stathmin could provide a pathogenetic mechanism able to explain the reported success of therapies aimed at promoting the stability of the microtubule network in demyelinating diseases (Moscarello et al, 2002). In agreement with this hypothesis, treatment of mice with active or passive experimental allergic encephalomyelitis (Cao et al, 2000;Pritzker and Moscarello, 1998) and of ND4 transgenics (Moscarello et al, 2002) with microtubule stabilizing drugs (i.e., Taxol) have shown a remarkable improvement in the neuropathology and clinical score.…”

Section: Discussionsupporting

confidence: 52%

“…In agreement with this hypothesis, treatment of mice with active or passive experimental allergic encephalomyelitis (Cao et al, 2000;Pritzker and Moscarello, 1998) and of ND4 transgenics (Moscarello et al, 2002) with microtubule stabilizing drugs (i.e., Taxol) have shown a remarkable improvement in the neuropathology and clinical score. Therefore, the results of the interdisciplinary and multifaceted experimental approach adopted in this study identify stathmin in particular and the microtubule network in general as an important target in demyelinating disorders.…”

Section: Discussionmentioning

confidence: 54%

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

Liu

Stadelmann²,

Moscarello³

et al. 2005

J. Neurosci.

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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.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 54%

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

Liu

Stadelmann²,

Moscarello³

et al. 2005

J. Neurosci.

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“…Transgenic ND4 mice (CD-1 strain) carrying 70 copies of the DM20 cDNA demyelinate spontaneously at 3 mo of age (25,26). EAE experiments used female 6-to 8-wk-old SJL mice (Charles River Breeding Laboratories, Wilmington, MA).…”

Section: Animals and Reagentsmentioning

confidence: 99%

“…three times weekly. Clinical scoring for ND4 was conducted, as described, with cumulative scores (range 0 -50) (26). Briefly, all animals were examined three times/week.…”

Section: Therapy Protocolsmentioning

confidence: 99%

Attenuation of Experimental Autoimmune Encephalomyelitis and Nonimmune Demyelination by IFN-β plus Vitamin B12: Treatment to Modify Notch-1/Sonic Hedgehog Balance

Mastronardi¹,

Min²,

Wang

et al. 2004

The Journal of Immunology

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Interferon-β is a mainstay therapy of demyelinating diseases, but its effects are incomplete in human multiple sclerosis and several of its animal models. In this study, we demonstrate dramatic improvements of clinical, histological, and laboratory parameters in in vivo mouse models of demyelinating disease through combination therapy with IFN-β plus vitamin B12 cyanocobalamin {B12CN) in nonautoimmune primary demyelinating ND4 (DM20) transgenics, and in acute and chronic experimental autoimmune encephalomyelitis in SJL mice. Clinical improvement (p values <0.0001) was paralleled by near normal motor function, reduced astrocytosis, and reduced demyelination. IFN-β plus B12CN enhanced in vivo and in vitro oligodendrocyte maturation. In vivo and in vitro altered expression patterns of reduced Notch-1 and enhanced expression of sonic hedgehog and its receptor were consistent with oligodendrocyte maturation and remyelination. IFN-β-B12CN combination therapy may be promising for the treatment of multiple sclerosis.

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“…a concerted effect. The enzymes involved in these modifications represent potential therapeutic targets as we have demonstrated recently with peptidylarginine deiminase and paclitaxel (Taxol) (47). …”

Section: Deiminated Arginine Residues In Mbp From Normal and Ms Tissumentioning

confidence: 99%

Multiple Sclerosis

Kim

Mastronardi

Wood

et al. 2003

Molecular & Cellular Proteomics

179

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Myelin basic protein (MBP) represents a candidate autoantigen in multiple sclerosis (MS). We isolated MBP from normal and MS human white matter and purified six components (charge isomers) to compare the post-translational modifications on each. The sites and extent of methylation, deimination, and phosphorylation were documented for all tryptic peptides by mass spectrometry. We found that mono and dimethylated arginine 107 was increased in MS samples; deimination of arginine occurred at a number of sites and was elevated in MS; phosphorylation was observed in 10 peptides in normal samples but was greatly reduced or absent in most peptides from MS samples. Data obtained with MBP isolated from fresh brain obtained from a spontaneously demyelinating mouse model supported the view that the changes observed in human brain were probably related to pathogenesis of demyelination, i.e. we found decreased phosphorylation and decreased amounts of glycogen synthesis kinase in brain homogenates using specific antibodies. This study represents the first to define post-translational modifications in demyelinating disease and suggest an important role in pathogenesis. Molecular & Cellular Proteomics 2:453-462, 2003. Multiple sclerosis (MS)1 is the most common demyelinating disease of the human central nervous system. It is multifactorial, requiring genetic, environmental (possibly viral), and immunological factors (1). Genetic screens of MS populations have failed to uncover a major susceptibility locus (2), suggesting that MS is a polygenic disease with each gene of small effect.Myelin basic protein (MBP), a major myelin protein that accounts for 35% of the total myelin protein, is a strong candidate autoantigen (3). It is a 170-amino acid protein in the human, containing 19 arginyl and 12 lysyl residues, which accounts for its basic character. It is devoid of cysteinyl residues, with a high proportion of disorder promoting amino acids such as A, R, G, Q, S, P, E, and K. It is a member of an expanding group of proteins that include the amyloid and prion proteins, considered to be intrinsically disordered (4), in which the disordered state is the functional state. Because of this, post-translational modifications determine the nature and extent of secondary structure, permitting the protein to adopt multiple conformations for a variety of binding events (5). Because interactions between the positive arginyl and lysyl residues and the negatively charged phosphate groups of the membrane phospholipids are essential to the structure of compact myelin, changes in positive charge of MBP would decrease the strength of these interactions (6).MBP is an unusual protein that has never been crystallized due to the myriad of post-translational modifications it possesses. These include phosphorylation, deamidation, deimination, arginine methylation, and N-terminal acylation. These give rise to a family of microheteromers or "charge isomers," several of which can be resolved by chromatography (7). The effects of some of these modifications o...

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Paclitaxel (Taxol) attenuates clinical disease in a spontaneously demyelinating transgenic mouse and induces remyelination

Cited by 40 publications

References 49 publications

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

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

Attenuation of Experimental Autoimmune Encephalomyelitis and Nonimmune Demyelination by IFN-β plus Vitamin B12: Treatment to Modify Notch-1/Sonic Hedgehog Balance

Multiple Sclerosis

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