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Oligodendrocyte injury in multiple sclerosis: a role for p53
Author(s) -
Wosik Karolina,
Antel Jack,
Kuhlmann Tanja,
Brück Wolfgang,
Massie Bernard,
Nalbantoglu Josephine
Publication year - 2003
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.01674.x
Subject(s) - oligodendrocyte , apoptosis , multiple sclerosis , myelin , programmed cell death , biology , fas ligand , tumor necrosis factor alpha , receptor , microbiology and biotechnology , immunology , cancer research , central nervous system , neuroscience , biochemistry
Multiple sclerosis (MS) is a neurological disorder characterized by myelin destruction and a variable degree of oligodendrocyte death. We have previously shown that overexpression of the transcription factor p53 can induce oligodendrocyte apoptosis. We investigated the mechanism of p53‐induced apoptosis using primary cultures of central nervous system‐derived adult human oligodendrocytes. Adenovirus‐mediated p53 overexpression resulted in up‐regulation of the death receptors Fas, DR4 and DR5 with subsequent caspase‐mediated apoptosis of the oligodendrocytes. The oligodendrocytes were protected from p53‐induced cell death by blocking signaling through Fas and/or tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) receptors. Although lower levels of p53 did not induce apoptosis, the increase in death receptor expression was sufficient to render the oligodendrocytes susceptible to apoptosis in the presence of exogenous Fas ligand and TRAIL. These ligands are present in the inflammatory milieu of active MS lesions. In situ analysis of active MS lesions revealed increased p53 expression in oligodendrocytes in lesions that featured oligodendrocyte apoptosis and cell loss. Our data provide evidence for a novel role for p53 in the pathogenesis of MS.