Caspase-3 activation in oligodendrocytes from the myelin-deficient rat

The myelin-deficient (MD) rat has a point mutation in its proteolipid prote in (PLP) gene that causes severe dysmyelination and oligodendrocyte cell de ath. Using an in vitro model, we have shown that MD oligodendrocytes initia lly differentiate similarly to wild-type cells, expressing galactocerebrosi de, 2',3'-cyclic nucleotide 3'-phosphodiesterase, and myelin basic protein. However, at the time when PLP expression would normally begin, the MD olig odendrocytes die via an apoptotic pathway involving caspase activation. The active form of caspase-3 was detected, along with the cleavage products of poly-(ADP-ribose) polymerase (PARP) and spectrin, major targets of caspase -mediated proteolysis. A specific inhibitor of casapse-3, Ac-DEVD-CMK, redu ced apoptosis in MD oligodendrocytes, but the rescued cells did not mature fully or express myelin-oligodendrocyte glycoprotein. These results suggest that mutant PLP affects not only cell death but also oligodendrocyte diffe rentiation. (C) 2001 Wiley-Liss, Inc.