Apaf1 mediates apoptosis and mitochondrial damage induced by mutant human SOD1s typical of familial amyotrophic lateral sclerosis.
Several studies have indicated that apoptotic pathways are responsible for the loss of motor neurons that constitute the hallmark of amyotrophic lateral sclerosis (ALS). In this study, we demonstrate that apoptosis induced by the expression of several mutant Cu,Zn superoxide dismutases (SOD1) typical of familial ALS is mediated by Apaf1, a scaffold protein involved in neural development. Using different cell lines of neuronal origin and modulating the expression of both mutant SOD1s and Apaf1, we show that the removal of Apaf1 prevents cells death. Interestingly, intercepting activation of the caspases cascade is also effective in preventing both the mitochondrial damage and the increase in the production of reactive oxygen species induced by fALS-SOD1, even in the presence of cytochrome c release. This death pathway may be crucial also for the pathogenesis of the sporadic form of the disease, where markers of increased oxidative stress and mitochondria damage have been found.
Cozzolino
Mauro
M
Lab. di Neurochimica, Centro di Neurobiologia Sperimentale Mondino-Tor Vergata-Santa Lucia, Rome, Italy.
Ferri
Alberto
A
Ferraro
Elisabetta
E
Rotilio
Giuseppe
G
Cecconi
Francesco
F
Carrì
Maria Teresa
MT
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053477:Apoptotic Protease-Activating Factor 1; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009447:Neuroblastoma; D018384:Oxidative Stress / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
C506592:APAF1 protein, human; C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C000606290:SOD1 protein, human; D045304:Cytochromes c; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1