Caspase-3 activation in oligodendrocytes from the myelin-deficient rat.
The myelin-deficient (MD) rat has a point mutation in its proteolipid protein (PLP) gene that causes severe dysmyelination and oligodendrocyte cell death. Using an in vitro model, we have shown that MD oligodendrocytes initially differentiate similarly to wild-type cells, expressing galactocerebroside, 2',3'-cyclic nucleotide 3'-phosphodiesterase, and myelin basic protein. However, at the time when PLP expression would normally begin, the MD oligodendrocytes 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, reduced 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 differentiation.
Beesley
J S
JS
Department of Neurology Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. beesley@email.chop.edu
Lavy
L
L
Eraydin
N B
NB
Siman
R
R
Grinspan
J B
JB
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003470:Culture Media / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D008297:Male; D018991:Myelin Proteolipid Protein / Q000172:deficiency* / Q000235:genetics; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism*; D017354:Point Mutation / Q000235:genetics; D051381:Rats; D011922:Rats, Mutant Strains
D061945:Caspase Inhibitors; D003470:Culture Media; D015853:Cysteine Proteinase Inhibitors; D018991:Myelin Proteolipid Protein; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases