Kv1.4 et la prolifération des oligodendrocytes

Un modèle murin a été développé pour mimer le développement de la sclérose en plaque, en utilisant des glycoprotéine d'oligodendrocyte. Eva Herrero Herranz et co-auteurs ont décrit la mise en place de motifs typique d'aggression sur les axones.

Neurobiol Dis. 2008 May;30(2):162-73. doi: 10.1016/j.nbd.2008.01.001. Epub 2008 Jan 26.

Pattern of axonal injury in murine myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis: implications for multiple sclerosis.

Herrero-Herranz E¹, Pardo LA, Gold R, Linker RA.

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Abstract

Axonal damage is a correlate for increasing disability in multiple sclerosis. Animal models such as experimental autoimmune encephalomyelitis (EAE) may help to develop better therapeutical neuroprotective strategies for the human disease. Here we investigate the pattern of axonal injury in murine myelin oligodendrocyte glycoprotein peptide 35-55 (MOG) induced EAE. Inflammatory infiltration, axonal densities and expression of amyloid precursor protein (APP), neurofilaments (SMI31 and 32) as well as expression of sodium channels were quantified in lesions, the perilesional area and normal appearing white matter (NAWM). Quantification of T cells and macrophages revealed a significant reduction of inflammatory infiltration at later disease stages despite an increase of demyelinated areas and persistent clinical disability. In lesions, axonal density was already significantly reduced early and throughout all investigated disease stages. A significant axonal loss was also seen in the grey matter and at later time points in the perilesion as well as NAWM. Numbers of axons characterized by non-phosphorylated neurofilaments and re-distribution of sodium channels 1.2 and 1.6 increased over the course of MOG-EAE whilst APP positive axons peaked at the maximum of disease. Finally, double-labeling experiments revealed a strong colocalization of sodium channels with APP, neurofilaments and the axonal nodal protein Caspr, but not glial and myelin markers in actively demyelinating lesions. In summary, progressive axonal loss distant from lesions is mainly associated with changes in neurofilament phosphorylation, re-distribution of sodium channels and demyelination. This axonal loss is dissociated from acute inflammatory infiltration and markedly correlates with clinical impairment. Consequently, therapeutic intervention may be promising at early stages of EAE focusing on inflammation, or later in disease targeting degenerative mechanisms.

Kv1.4 et la sclérose en plaque

Dans un étude de 2007, Eva Herrero Herranz et ces co-auteurs ont montré le rôle de Kv1.4 au cours de la démyélinisation.

http://www.ncbi.nlm.nih.gov/pubmed/17600124

Am J Pathol. 2007 Aug;171(2):589-98. Epub 2007 Jun 28.

Re-expression of a developmentally restricted potassium channel in autoimmune demyelination: Kv1.4 is implicated in oligodendroglial proliferation.

Herrero-Herranz E¹, Pardo LA, Bunt G, Gold R, Stühmer W, Linker RA.

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Abstract

Mechanisms of lesion repair in multiple sclerosis are incompletely understood. To some degree, remyelination can occur, associated with an increase of proliferating oligodendroglial cells. Recently, the expression of potassium channels has been implicated in the control of oligodendrocyte precursor cell proliferation in vitro. We investigated the expression of Kv1.4 potassium channels in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis, a model of multiple sclerosis. Confocal microscopy revealed expression of Kv1.4 in AN2-positive oligodendrocyte precursor cells and premyelinating oligodendrocytes in vitro but neither in mature oligodendrocytes nor in the spinal cords of healthy adult mice. After induction of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis, Kv1.4 immunoreactivity was detected in or around lesions already during disease onset with a peak early and a subsequent decrease in the late phase of the disease. Kv1.4 expression was confined to 2',3'-cyclic nucleotide 3'-phosphodiesterase-positive oligodendroglial cells, which were actively proliferating and ensheathed naked axons. After a demyelinating episode, the number of Kv1.4 and 2',3'-cyclic nucleotide 3'-phosphodiesterase double-positive cells was greatly reduced in ciliary neurotrophic factor knockout mice, a model with impaired lesion repair. In summary, the re-expression of an oligodendroglial potassium channel may have a functional implication on oligodendroglial cell cycle progression, thus influencing tissue repair in experimental autoimmune encephalomyelitis and multiple sclerosis.