The α- to γ-enolase switch: The role and regulation of γ-enolase during oligodendrocyte differentiation.

The glycolytic enzyme γ-enolase is a highly specific neuronal marker that is known to replace ubiquitously expressed α-enolase in the brain. Moreover, γ-enolase has been shown to exert neurotrophic activity, which is regulated by cathepsin X, a lysosomal peptidase. This study investigates the role of γ-enolase and its regulation by cathepsin X during the differentiation of oligodendrocytes, which are essential for normal brain function. We established a differentiation protocol for the human oligodendroglioma (HOG) cell line and demonstrated for the first time that an α- to γ-enolase switch occurs during HOG cell differentiation. This switch was confirmed by the expression of specific markers underscoring the role of γ-enolase in oligodendrocyte differentiation. Moreover, γ-enolase overexpression enhanced oligodendrocyte differentiation, while silencing of γ-enolase by siRNA significantly decreased maturation marker. Further, the regulatory role of cysteine peptidase cathepsin X on γ-enolase function was found. Silencing cathepsin X significantly changed cell morphology, enhanced oligodendrocyte differentiation, altered the expression of oligodendrocyte markers, and increased levels of the active form of γ-enolase. Inhibiting cathepsin X similarly changed cell morphology and enhanced oligodendrocyte differentiation. These findings suggest that cathepsin X modulates γ-enolase activity and thereby influences oligodendrocyte differentiation and thus neuronal function.