Oligodendrocyte injury in multiple sclerosis: a role for p53

Abstract

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.

Inhibition of p53 Transcriptional Activity: A Potential Target for Future Development of Therapeutic Strategies for Primary Demyelination

“…An additional difference between these two neuropathological findings is the presence of remyelination attempts that are frequently detected in the immunemediated forms and are less prominent in cases with extensive oligodendrogliopathy (Lucchinetti et al, 2000). Very little is known regarding the causes of oligodendroglial death in MS patients; however, increased levels of the pro-apoptotic transcription factor p53 and of its downstream genes have been detected in cases characterized by oligodendrogliopathy, microglial infiltration, and relative lack of remyelination (Kuhlmann et al, 2002;Aboul-Enein et al, 2003;Wosik et al, 2003;Stadelmann et al, 2005). Studies in cultured human oligodendrocytes further identified p53 as a critical pro-apoptotic effector (Ladiwala et al, 1999;Wosik et al, 2003).…”

“…Very little is known regarding the causes of oligodendroglial death in MS patients; however, increased levels of the pro-apoptotic transcription factor p53 and of its downstream genes have been detected in cases characterized by oligodendrogliopathy, microglial infiltration, and relative lack of remyelination (Kuhlmann et al, 2002;Aboul-Enein et al, 2003;Wosik et al, 2003;Stadelmann et al, 2005). Studies in cultured human oligodendrocytes further identified p53 as a critical pro-apoptotic effector (Ladiwala et al, 1999;Wosik et al, 2003). We thereby hypothesized that this transcription factor could play a very important role in models of primary demyelination consequent to oligodendrocyte dystrophy.…”

Protective effects of estradiol on TRAIL-induced apoptosis in a human oligodendrocytic cell line: evidence for multiple sites of interactions

“…In this line, recent observations suggest that the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) could play a role in the pathogenesis of MS, as its increased activity is associated with detrimental effects on oligodendrocytes. 7,8 TRAIL is a recently characterized member of the TNF superfamily that binds to five specific membrane receptors. 9,10 Among these, receptors DR4 and DR5 are type I membrane proteins and belong to the TNF/NGF receptors superfamily.…”

Cyclin-dependent kinase inhibitor flavopiridol promotes remyelination in a cuprizone induced demyelination model

“…Moreover, p53 knock out or pharmacological inhibition of p53 decreased the extent of demyelination. 40,41 SLFN1 has been shown to cause growth inhibition and a G1 cell cycle arrest in murine fibroblasts, while other reports suggested that SLFN1 was associated with immune response, but without anti-proliferative activities. 42 The only one down-regulated gene in CPZ-exposed mice was Mre11a.…”