Selective inhibition of caspases in skeletal muscle reverses the apoptotic synaptic degeneration in slow-channel myasthenic syndrome.
Slow-channel syndrome (SCS) is a congenital myasthenic disorder caused by point mutations in subunits of skeletal muscle acetylcholine receptor leading to Ca(2+) overload and degeneration of the postsynaptic membrane, nuclei and mitochondria of the neuromuscular junction (NMJ). In both SCS muscle biopsies and transgenic mouse models for SCS (mSCS), the endplate regions are shrunken, and there is evidence of DNA damage in the subsynaptic region. Activated caspase-9, -3 and -7 are intensely co-localized at the NMJ, and the Ca(2+)-activated protease, calpain, and the atypical cyclin-dependent kinase (Cdk5) are overactivated in mSCS. Thus, the true mediator(s) of the disease process is not clear. Here, we demonstrate that selective inhibition of effector caspases, caspase-3 and -7, or initiator caspase, caspase-9, in limb muscle in vivo by localized expression of recombinant inhibitor proteins dramatically decreases subsynaptic DNA damage, increases endplate area and improves ultrastructural abnormalities in SCS transgenic mice. Calpain and Cdk5 are not affected by this treatment. On the other hand, inhibition of Cdk5 by expression of a dominant-negative form of Cdk5 has no effect on the degeneration. Together with previous studies, these results indicate that focal activation of caspase activity at the NMJ is the principal pathological process responsible for the synaptic apoptosis in SCS. Thus, treatments that reduce muscle caspase activity are likely to be of benefit for SCS patients.
Department of Neurology and.
Haipeng
H
Zhu
Peter
P
Pytel
Christopher M
CM
Gomez
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002154:Calpain / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism*; D053179:Caspase 7 / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism*; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D004249:DNA Damage; D004195:Disease Models, Animal; D005121:Extremities / Q000503:physiopathology*; D005786:Gene Expression Regulation; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009045:Motor Endplate / Q000503:physiopathology*; D018482:Muscle, Skeletal / Q000378:metabolism*; D020294:Myasthenic Syndromes, Congenital / Q000201:enzymology / Q000503:physiopathology*
D051034:Inhibitor of Apoptosis Proteins; D051360:Cyclin-Dependent Kinase 5; D002154:Calpain; D053148:Caspase 3; D053179:Caspase 7; D053453:Caspase 9