Inhibition of apoptosome activation protects injured motor neurons from cell death.
Within the mammalian central nervous system many forms of neurodegenerative injury are regulated via programmed cell death, a highly conserved program of cellular suicide. Programmed cell death is regulated by multiple signaling pathways, which have been identified within mammalian cells, although several lines of evidence suggest that the intrinsic pathway predominantly regulates the death of motor neurons following acute injury in vivo. We have tested this hypothesis by performing facial axotomies on cytochrome c knock-in mice containing a point mutation in the genomic locus of cytochrome c resulting in a lysine to alanine conversion at position 72 of the protein. The introduced mutation inhibits the ability of cytochrome c to induce the formation of the apoptosome, a protein complex that is principally required for the activation of the intrinsic pathway, but does not alter its function in oxidative phosphorylation. Homozygous cytochrome c knock-in mutants displayed a significant enhancement in motor neuron survival following injury when compared with littermate controls, thus establishing the apoptosome as a viable target for protecting motor neurons from neural injury. However, protection of facial motor neurons differs from that previously reported in mice either overexpressing anti-apoptotic or lacking pro-apoptotic members of the Bcl-2 family, which are thought to regulate several aspects of mitochondrial dysfunction including the release of cytochrome c from the mitochondria to the cytoplasm. Therefore, these results directly demonstrate for the first time the influence of the apoptosome on injury-induced neuronal programmed cell death in vivo isolated from upstream Bcl-2 family-mediated effects.
Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
Anish Kumar
AK
Kanungo
Zhenyue
Z
Hao
Andrew James
AJ
Elia
Tak Wah
TW
Mak
Jeffrey Theodore
JT
Henderson
D000818:Animals; D053478:Apoptosomes / Q000378:metabolism*; D019771:Axotomy; D053148:Caspase 3 / Q000235:genetics; D016923:Cell Death; D045304:Cytochromes c / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000166:cytology* / Q000378:metabolism*; D020800:Receptor, Nerve Growth Factor / Q000235:genetics
D053478:Apoptosomes; D020800:Receptor, Nerve Growth Factor; D045304:Cytochromes c; C505409:Casp3 protein, mouse; D053148:Caspase 3