Apoptosis in retinal degeneration involves cross-talk between apoptosis-inducing factor (AIF) and caspase-12 and is blocked by calpain inhibitors.
Molecular mechanisms underlying apoptosis in retinitis pigmentosa, as in other neurodegenerative diseases, are still elusive, and this fact hampers the development of a cure for this blinding disease. We show that two apoptotic pathways, one from the mitochondrion and one from the endoplasmic reticulum, are coactivated during the degenerative process in an animal model of retinitis pigmentosa, the rd1 mouse. We found that both AIF and caspase-12 translocate to the nucleus of dying photoreceptors in vivo and in an in vitro cellular model. Translocation of both apoptotic factors depends on changes in intracellular calcium homeostasis and on calpain activity. Knockdown experiments defined that AIF plays the major role in this apoptotic event, whereas caspase-12 has a reinforcing effect. This study provides a link between two executor caspase-independent apoptotic pathways involving mitochondrion and endoplasmic reticulum in a degenerating neuron.
Sanges
Daniela
D
Telethon Institute of Genetics and Medicine (TIGEM), 80131 Naples, Italy.
Comitato
Antonella
A
Tammaro
Roberta
R
Marigo
Valeria
V
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002154:Calpain / Q000378:metabolism; D053454:Caspase 12 / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D006023:Glycoproteins / Q000494:pharmacology*; D051379:Mice; D010786:Photoreceptor Cells / Q000378:metabolism / Q000473:pathology; D012162:Retinal Degeneration / Q000201:enzymology* / Q000473:pathology*
D051033:Apoptosis Inducing Factor; D002121:Calcium Channel Blockers; D006023:Glycoproteins; C039304:calpain inhibitors; D002154:Calpain; D053454:Caspase 12; D002118:Calcium