title: Calpain and PARP activation during photoreceptor cell death in P23H and S334ter rhodopsin mutant rats.
abstract: Retinitis pigmentosa (RP) is a heterogeneous group of inherited neurodegenerative diseases affecting photoreceptors and causing blindness. Many human cases are caused by mutations in the rhodopsin gene. An important question regarding RP pathology is whether different genetic defects trigger the same or different cell death mechanisms. To answer this question, we analysed photoreceptor degeneration in P23H and S334ter transgenic rats carrying rhodopsin mutations that affect protein folding and sorting respectively. We found strong activation of calpain and poly(ADP-ribose) polymerase (PARP) in both mutants, concomitant with calpastatin down-regulation, increased oxidative DNA damage and accumulation of PAR polymers. These parameters were strictly correlated with the temporal progression of photoreceptor degeneration, mirroring earlier findings in the phosphodiesterase-6 mutant rd1 mouse, and suggesting execution of non-apoptotic cell death mechanisms. Interestingly, activation of caspases-3 and -9 and cytochrome c leakage-key events in apoptotic cell death--were observed only in the S334ter mutant, which also showed increased expression of PARP-1. The identification of the same metabolic markers triggered by different mutations in two different species suggests the existence of common cell death mechanisms, which is a major consideration for any mutation independent treatment.
authors.affiliation: Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
authors.forename: Jasvir
authors.initials: J
authors.lastname: Kaur
authors.forename: Stine
authors.initials: S
authors.lastname: Mencl
authors.forename: Ayse
authors.initials: A
authors.lastname: Sahaboglu
authors.forename: Pietro
authors.initials: P
authors.lastname: Farinelli
authors.forename: Theo
authors.initials: T
authors.lastname: van Veen
authors.forename: Eberhart
authors.initials: E
authors.lastname: Zrenner
authors.forename: Per
authors.initials: P
authors.lastname: Ekström
authors.forename: François
authors.initials: F
authors.lastname: Paquet-Durand
authors.forename: Blanca
authors.initials: B
authors.lastname: Arango-Gonzalez
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002154:Calpain / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D016923:Cell Death; D048430:Cell Shape; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage; D004789:Enzyme Activation; D006801:Humans; D020287:In Situ Nick-End Labeling; D009154:Mutation / Q000235:genetics*; D018384:Oxidative Stress; D020419:Photoreceptor Cells, Vertebrate / Q000166:cytology* / Q000201:enzymology*; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D011922:Rats, Mutant Strains; D055647:Rats, Transgenic; D012243:Rhodopsin / Q000235:genetics*; D013194:Staining and Labeling
chemical_list: D015415:Biomarkers; D002135:Calcium-Binding Proteins; D011064:Poly Adenosine Diphosphate Ribose; C033668:calpastatin; D045304:Cytochromes c; D012243:Rhodopsin; D011065:Poly(ADP-ribose) Polymerases; D002154:Calpain; D053148:Caspase 3; D053453:Caspase 9