Demyelination in a transgenic mouse: A model for multiple sclerosis

Mastronardi, Fabrizio G.; Ackerley, Cameron; Arsenault, Larry; Roots, Betty I.; Moscarello, Mario A.

doi:10.1002/jnr.490360309

Cited by 83 publications

(84 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar results were also obtained in a transgenic mouse model of spontaneous demyelination, the ND4 mouse (Mastronardi et al, 1993(Mastronardi et al, , 1996. In these animals, stathmin immunoreactivity was observed in damaged oligodendrocytes in the corpus callosum and in protein extracts from the myelin fraction (data not shown).…”

Section: Discussionsupporting

confidence: 81%

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

Liu

Stadelmann²,

Moscarello³

et al. 2005

J. Neurosci.

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 81%

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

Liu

Stadelmann²,

Moscarello³

et al. 2005

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…ND4 transgenic mice have been described previously (Mastronardi et al, 1993(Mastronardi et al, , 1996Moscarello et al, 2002). They contain 70 copies of the cDNA for the myelin-associated proteolipid protein (PLP) DM20.…”

Section: Methodsmentioning

confidence: 99%

“…These mice have been described previously (Mastronardi et al, 1993(Mastronardi et al, , 1996Moscarello et al, 2002). They have a normal period of development up to 3 months after birth and thereafter develop a chronic progressive primary CNS demyelination.…”

Section: Nuclear Pad4 and Tnf-␣ Are Increased Before Clinical Diseasementioning

confidence: 99%

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

Mastronardi¹,

Wood²,

Jiang³

et al. 2006

J. Neurosci.

Self Cite

229

175

View full text Add to dashboard Cite

Modification of arginine residues by citrullination is catalyzed by peptidylarginine deiminases (PADs), of which five are known, generating irreversible protein structural modifications. We have shown previously that enhanced citrullination of myelin basic protein contributed to destabilization of the myelin membrane in the CNS of multiple sclerosis (MS) patients. We now report increased citrullination of nucleosomal histones by PAD4 in normal-appearing white matter (NAWM) of MS patients and in animal models of demyelination. Histone citrullination was attributable to increased levels and activity of nuclear PAD4. PAD4 translocation into the nucleus was attributable to elevated tumor necrosis factor-␣ (TNF-␣) protein. The elevated TNF-␣ in MS NAWM was not associated with CD3 ϩ or CD8 ϩ lymphocytes, nor was it associated with CD68 ϩ microglia/macrophages. GFAP, a measure of astrocytosis, was the only cytological marker that was consistently elevated in the MS NAWM, suggesting that TNF-␣ may have been derived from astrocytes. In cell cultures of mouse and human oligodendroglial cell lines, PAD4 was predominantly cytosolic but TNF-␣ treatment induced its nuclear translocation. To address the involvement of TNF-␣ in targeting PAD4 to the nucleus, we found that transgenic mice overexpressing TNF-␣ also had increased levels of citrullinated histones and elevated nuclear PAD4 before demyelination. In conclusion, high citrullination of histones consequent to PAD4 nuclear translocation is part of the process that leads to irreversible changes in oligodendrocytes and may contribute to apoptosis of oligodendrocytes in MS.

show abstract

“…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%

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

View full text Add to dashboard Cite

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.

show abstract

Demyelination in a transgenic mouse: A model for multiple sclerosis

Cited by 83 publications

References 14 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

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

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

Contact Info

Product

Resources

About