Apoptosis in Retinal Degeneration Involves Cross-talk Between Apoptosis-inducing Factor (AIF) and Caspase-12 and is Blocked by Calpain Inhibitors

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2006 Nov 8

PMID 17088543

Citations 104

Authors

Daniela Sanges

Antonella Comitato

Roberta Tammaro

Valeria Marigo

Affiliations

Soon will be listed here.

Abstract

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.

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References

Wassle H, Grunert U, Cook N, Molday R . The cGMP-gated channel of rod outer segments is not localized in bipolar cells of the mammalian retina. Neurosci Lett. 1992; 134(2):199-202. DOI: 10.1016/0304-3940(92)90516-a. View

Wootz H, Hansson I, Korhonen L, Napankangas U, Lindholm D . Caspase-12 cleavage and increased oxidative stress during motoneuron degeneration in transgenic mouse model of ALS. Biochem Biophys Res Commun. 2004; 322(1):281-6. DOI: 10.1016/j.bbrc.2004.07.118. View

Polster B, Basanez G, Etxebarria A, Hardwick J, Nicholls D . Calpain I induces cleavage and release of apoptosis-inducing factor from isolated mitochondria. J Biol Chem. 2004; 280(8):6447-54. DOI: 10.1074/jbc.M413269200. View

Pearce-Kelling S, Aleman T, Nickle A, Laties A, Aguirre G, Jacobson S . Calcium channel blocker D-cis-diltiazem does not slow retinal degeneration in the PDE6B mutant rcd1 canine model of retinitis pigmentosa. Mol Vis. 2001; 7:42-7. View

Klein J, Longo-Guess C, Rossmann M, Seburn K, Hurd R, Frankel W . The harlequin mouse mutation downregulates apoptosis-inducing factor. Nature. 2002; 419(6905):367-74. DOI: 10.1038/nature01034. View

Hetz C, Russelakis-Carneiro M, Maundrell K, Castilla J, Soto C . Caspase-12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein. EMBO J. 2003; 22(20):5435-45. PMC: 213791. DOI: 10.1093/emboj/cdg537. View

Frasson M, Sahel J, Fabre M, Simonutti M, Dreyfus H, Picaud S . Retinitis pigmentosa: rod photoreceptor rescue by a calcium-channel blocker in the rd mouse. Nat Med. 1999; 5(10):1183-7. DOI: 10.1038/13508. View

Cande C, Vahsen N, Garrido C, Kroemer G . Apoptosis-inducing factor (AIF): caspase-independent after all. Cell Death Differ. 2004; 11(6):591-5. DOI: 10.1038/sj.cdd.4401400. View

Cook N, Molday L, Reid D, Kaupp U, Molday R . The cGMP-gated channel of bovine rod photoreceptors is localized exclusively in the plasma membrane. J Biol Chem. 1989; 264(12):6996-9. View

10.

Bowes C, Li T, Danciger M, Baxter L, Applebury M, Farber D . Retinal degeneration in the rd mouse is caused by a defect in the beta subunit of rod cGMP-phosphodiesterase. Nature. 1990; 347(6294):677-80. DOI: 10.1038/347677a0. View

11.

Fujita E, Kouroku Y, Jimbo A, Isoai A, Maruyama K, Momoi T . Caspase-12 processing and fragment translocation into nuclei of tunicamycin-treated cells. Cell Death Differ. 2002; 9(10):1108-14. DOI: 10.1038/sj.cdd.4401080. View

12.

Zeiss C, Neal J, Johnson E . Caspase-3 in postnatal retinal development and degeneration. Invest Ophthalmol Vis Sci. 2004; 45(3):964-70. DOI: 10.1167/iovs.03-0439. View

13.

Doonan F, Donovan M, Cotter T . Caspase-independent photoreceptor apoptosis in mouse models of retinal degeneration. J Neurosci. 2003; 23(13):5723-31. PMC: 6741277. View

14.

Pawlyk B, Li T, Scimeca M, Sandberg M, Berson E . Absence of photoreceptor rescue with D-cis-diltiazem in the rd mouse. Invest Ophthalmol Vis Sci. 2002; 43(6):1912-5. View

15.

Cande C, Cecconi F, Dessen P, Kroemer G . Apoptosis-inducing factor (AIF): key to the conserved caspase-independent pathways of cell death?. J Cell Sci. 2002; 115(Pt 24):4727-34. DOI: 10.1242/jcs.00210. View

16.

Tropepe V, COLES B, Chiasson B, Horsford D, Elia A, McInnes R . Retinal stem cells in the adult mammalian eye. Science. 2000; 287(5460):2032-6. DOI: 10.1126/science.287.5460.2032. View

17.

Chu C, Zhu J, Cao G, Signore A, Wang S, Chen J . Apoptosis inducing factor mediates caspase-independent 1-methyl-4-phenylpyridinium toxicity in dopaminergic cells. J Neurochem. 2005; 94(6):1685-95. PMC: 1868549. DOI: 10.1111/j.1471-4159.2005.03329.x. View

18.

Susin S, Lorenzo H, Zamzami N, Marzo I, Snow B, Brothers G . Molecular characterization of mitochondrial apoptosis-inducing factor. Nature. 1999; 397(6718):441-6. DOI: 10.1038/17135. View

19.

Farber D, Lolley R . Cyclic guanosine monophosphate: elevation in degenerating photoreceptor cells of the C3H mouse retina. Science. 1974; 186(4162):449-51. DOI: 10.1126/science.186.4162.449. View

20.

McLaughlin M, Sandberg M, Berson E, Dryja T . Recessive mutations in the gene encoding the beta-subunit of rod phosphodiesterase in patients with retinitis pigmentosa. Nat Genet. 1993; 4(2):130-4. DOI: 10.1038/ng0693-130. View