Cell death in the oligodendrocyte lineage: A molecular perspective of life/death decisions in development and disease

Abstract

Cell death in the oligodendrocyte lineage occurs during development and in pathological conditions as the result of a balance between opposing molecular signals. This review focuses on the molecular mechanisms of activation of signal transduction pathways affecting life/death decisions in progenitor cells and in mature oligodendrocytes. Loss of trophic support, cytokine receptor activation, and oxidative stress may differentially contribute to the induction of cell death at specific stages of development and to the pathogenesis of demyelinating disorders. The execution of the death program leading to the morphological changes of apoptosis and/or necrosis is then determined by the generation of reactive oxygen species and the level of impairment of mitochondrial function. The final decision of a cell to die or survive is determined by a competition between survival and death signals. Depending on ligand availability, type, and levels of receptor expression and downstream cross-talks between distinct signaling pathways, the cell may activate a death execution program that will be affected by its stage of differentiation and its energetic metabolism.

Synergistic activity of interleukin-17 and tumor necrosis factor-α enhances oxidative stress-mediated oligodendrocyte apoptosis

“…Because OL degeneration is reported to be associated with oxidative stress (Casaccia‐Bonnefil 2000; Jana and Pahan 2005), we next investigated whether ROS (oxidative stress) generation is involved in IL‐17 and TNF‐α‐induced OL apoptosis. Cytokine‐treated B12 cells were incubated with the fluorescent dye CM‐DCFDA, which is oxidized in the presence of cellular oxidative stress.…”

Molecular mechanisms of enhanced susceptibility to apoptosis in differentiating oligodendrocytes

“…The present study was designed to examine possible differences in the expression levels of components of the apoptotic machinery, which could explain the enhanced susceptibility of differentiated oligodendrocytes to apoptosis. The hallmark of apoptotic death is the activation of proteolytic enzymes called executor caspases (for review see Casaccia‐Bonnefil, 2000). Executor caspases are present in cells as proenzymes, which are activated through proteolytic cleavage by initiator caspases.…”

“…Because mitochondrial release of cytochrome C is modulated by the Bcl2/Bad/Bax system (for review see Casaccia‐Bonnefil, 2000), we next focused our analysis on the developmental profile of proteins regulating mitochondrial permeability. The expression of Bcl2 and Bcl XL was examined during the course of oligodendrocyte differentiation, because both proteins have the ability to form cation‐selective pores in the mitochondrial membrane.…”

“…In the adult brain, spinal cord injury and demyelinating disorders can induce apoptosis of mature oligodendrocytes (for review see Casaccia‐Bonnefil, 2000). After injury, several inflammatory cytokines are released, including tumor necrosis factor (TNF) and nerve growth factor (NGF).…”

“…Upon binding of the ligand to its receptor, specific apoptotic “activators” are recruited to the membrane via the death domain, and this event allows recruitment of inactive proteolytic enzymes called procaspases (Chinnaiyan et al, 1995; Hsu et al, 1995). Initiation of the proteolytic cascade leads to the “execution” of the apoptotic program (for review see Casaccia‐Bonnefil, 2000). Activation of p55TNFR and p75NGFR has been shown to elicit apoptosis in mature oligodendrocytes but not in immature oligodendrocyte progenitors (Merrill, 1991; D'Souza et al, 1995; McLaurin et al, 1995; Probert et al, 1995; Casaccia‐Bonnefil et al, 1996; Akaglossu et al, 1998; Cammer, 2000; Back et al, 2001).…”