Mechanism of CAR syndrome: anti-recoverin antibodies are the inducers of retinal cell apoptotic death via the caspase 9- and caspase 3-dependent pathway.
Anti-recoverin autoantibodies have been associated with cancer-associated retinopathy (CAR), a paraneoplastic blinding disease. Those antibodies have been shown to induce apoptotic death of photoreceptor cells. The objective was to ascertain the mechanisms of retinal death induced by anti-recoverin antibody in vitro by examining the apoptotic pathway involved in retinal cell death. Internalization of anti-recoverin antibody or its Fab fragments by retinal cells mediated by endocytosis lead to cytotoxicity. Antibody cellular translocation induced the increase of bcl-x(s) and bax and the decrease in the bcl-x(L) protein. We detected the release of cytochrome c and down-regulation of the apaf-1 protein. This correlated with the sequential activation of caspase 9 and caspase 3, as well as the degradation of the caspase substrate PARP and the fragmentation of DNA. Our data show that anti-recoverin antibodies are inducers of apoptosis through the mitochondrial pathway involving caspases 9 and 3. We propose that a similar mechanism may be in place in patients with CAR syndrome where high levels of circulating antibodies have been associated with retinal degeneration.
Shiraga
Sharon
S
Neurological Sciences Institute, Oregon Health and Science University, Portland, OR 97201, USA.
Adamus
Grazyna
G
D000818:Animals; D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1; D001323:Autoantibodies / Q000276:immunology*; D002135:Calcium-Binding Proteins / Q000276:immunology*; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000502:physiology*; D003574:Cytochrome c Group / Q000378:metabolism; D053938:DNA Fragmentation; D004789:Enzyme Activation; D005136:Eye Proteins; D051597:Hippocalcin; D008074:Lipoproteins; D009419:Nerve Tissue Proteins; D010257:Paraneoplastic Syndromes / Q000209:etiology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011506:Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051381:Rats; D051603:Recoverin; D012160:Retina / Q000473:pathology*; D012162:Retinal Degeneration / Q000209:etiology*
C506594:Apaf1 protein, rat; D053477:Apoptotic Protease-Activating Factor 1; D001323:Autoantibodies; D002135:Calcium-Binding Proteins; D003574:Cytochrome c Group; D005136:Eye Proteins; D008074:Lipoproteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C496733:Rcvrn protein, rat; D051603:Recoverin; D051597:Hippocalcin; D011065:Poly(ADP-ribose) Polymerases; C505410:Casp3 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases