Exogenous myelin basic protein promotes oligodendrocyte death via increased calcium influx

Abstract

Treatment of cultured oligodendrocytes (OLGs) with micromolar quantities of myelin basic protein (MBP) caused a rapid, MBP-dose-dependent cell death. In contrast, a 72-hr incubation of OLGs with MBP peptides (1-44, 47-87, 88-151, or 152-167) at comparable concentrations had no effect on cell viability. MBP and MBP peptides (1-44 and 88-151) have been shown to interact with ganglioside GM1 (Tzeng et al.: J Neurochem Res: 42:758-767, 1995). This interaction has been reported to increase calcium influx. Therefore, using the fluorescent dye Indo-1 and an ACAS laser cytometer, we examined the level of intracellular calcium in OLGs after MBP treatment. MBP was shown to provoke a rapid, dramatic, and sustained rise of intracellular calcium in most OLGs. The levels of elevated intracellular calcium were sustained and did not return to baseline even after 10 min. This increase of intracellular calcium was suppressed in the presence of EGTA, indicating that the [Ca2+]i rise was due to the entry of extracellular calcium. Incubation of cultured OLGs with MBP peptides (1-44 or 88-151) caused a modest and transitory elevation of intracellular calcium ions in a lower percentage of OLGs. The potent OLG cytotoxicity of intact MBP and the loss of potency after proteolysis raise the possibility that MBP proteolysis during demyelination protects OLGs from death.

Increased Expression of Golli Myelin Basic Proteins Enhances Calcium Influx into Oligodendroglial Cells

“…It has been reported that classic MBP and MBP peptides (1-44 and 88-151) interact with ganglioside GM1, and this interaction can lead to an increase Ca 2ϩ influx in OLs (Tzeng et al, 1995). However, previous transfection with the BG21 MBP domain studies showed no morphological changes (Reyes and Campagnoni, 2002), and there are no Ca 2ϩ changes associated with transfection of the J37 MBP domain into N19 cells (our unpublished data).…”

Trophic effect of cholera toxin B subunit in cultured cerebellar granule neurons: Modulation of intracellular calcium by GM1 ganglioside

“…Alternatively, the possibility of indirect modulatory effects may be considered, such as activation or inhibition of a kinase which alters channel properties; several examples of kinase modulation by GM1 (and other gangliosides) have been reported (Kreutter et al, 1987;Chan, 1987;Nagai and Tsuji, 1988;Yates et al, 1989;Higashi and Yamagata, 1992). Current efforts in several laboratories have identified a number of proteins which bind to GM1, some of which represent associations of known functional consequences (Cochran et al, 1983;Fueshko and Schengrund, 1992;Saito and Yu, 1993;Siege1 and Suzuki, 1994;Saito et al, 1994;Tzeng et al, 1995). It remains to be elucidated in more precise molecular terms how GMl interacts with the various proteins involved in Ca2+ flux and the maintenance of Ca2+ homeostasis.…”

Calcium signalling in cells of oligodendroglial lineage

“…Contact with myelin or with another OLG results in the collapse of the fine structure of OLG processes, which is preceded by an increase in Ca 2ϩ that is prevented by pertussis-toxin (Moorman and Hume, 1994). Exposure to myelin basic protein induces sustained Ca 2ϩ influx and cell death in OLGs and produces demyelination (Althaus et al, 2000;Tzeng et al, 1995). It can be argued that such a response may enable OLGs to recognize each other during development and prevent myelination of the same axonal segment by two OLGs.…”