Clostridium perfringens Epsilon Toxin Causes Selective Death of Mature Oligodendrocytes and Central Nervous System Demyelination

J.R.L. and Y.M. contributed equally to this article. ABSTRACT Clostridium perfringens epsilon toxin (-toxin) is responsible for a devastating multifocal central nervous system (CNS) white matter disease in ruminant animals. The mechanism by which -toxin causes white matter damage is poorly under-stood. In this study, we sought to determine the molecular and cellular mechanisms by which -toxin causes pathological changes to white matter. In primary CNS cultures, -toxin binds to and kills oligodendrocytes but not astrocytes, microglia, or neurons. In cerebellar organotypic culture, -toxin induces demyelination, which occurs in a time- and dose-dependent manner, while preserving neurons, astrocytes, andmicroglia. -Toxin specificity for oligodendrocytes was confirmed using enriched glial culture. Sensitivity to -toxin is developmentally regulated, as only mature oligodendrocytes are susceptible to -toxin; oligo-dendrocyte progenitor cells are not. -Toxin sensitivity is also dependent on oligodendrocyte expression of the proteolipid my-elin and lymphocyte protein (MAL), as MAL-deficient oligodendrocytes are insensitive to -toxin. In addition, -toxin binding to white matter follows the spatial and temporal pattern of MAL expression. A neutralizing antibody against -toxin inhibits oligodendrocyte death and demyelination. This study provides several novel insights into the action of -toxin in the CNS. (i) -Toxin causes selective oligodendrocyte death while preserving all other neural elements. (ii) -Toxin-mediated oligodendro-cyte death is a cell autonomous effect. (iii) The effects of -toxin on the oligodendrocyte lineage are restricted to mature oligo-dendrocytes. (iv) Expression of the developmentally regulated proteolipid MAL is required for the cytotoxic effects. (v) The cyto