Inhibitory peptide of mitochondrial μ-calpain protects against photoreceptor degeneration in rhodopsin transgenic S334ter and P23H rats.

Abstract

Mitochondrial μ-calpain and apoptosis-inducing factor (AIF)-dependent photoreceptor cell death has been seen in several rat and mouse models of retinitis pigmentosa (RP). Previously, we demonstrated that the specific peptide inhibitor of mitochondrial μ-calpain, Tat-µCL, protected against retinal degeneration following intravitreal injection or topical eye-drop application in Mertk gene-mutated Royal College of Surgeons rats, one of the animal models of RP. Because of the high rate of rhodopsin mutations in RP patients, the present study was performed to confirm the protective effects of Tat-µCL against retinal degeneration in rhodopsin transgenic S334ter and P23H rats. We examined the effects of intravitreal injection or topical application of the peptide on retinal degeneration in S334ter and P23H rats by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, electroretinogram (ERG), immunohistochemistry for AIF, and histological staining. In S334ter rats, we found that intravitreal injection or topical application of the peptide prevented photoreceptor cell death from postnatal (PN) 15 to 18 days, the time of early-stage retinal degeneration. Topical application of the peptide also delayed attenuation of ERG responses from PN 28 to 56 days. In P23H rats, topical application of the peptide protected against photoreceptor cell death and nuclear translocation of AIF on PN 30, 40, and 50 days, as the primary stages of degeneration. We observed that topical application of the peptide inhibited the thinning of the outer nuclear layer and delayed ERG attenuations from PN 30 to 90 days. Our results demonstrate that the mitochondrial μ-calpain and AIF pathway is involved in early-stage retinal degeneration in rhodopsin transgenic S334ter and P23H rats, and inhibition of this pathway shows curative potential for rhodopsin mutation-caused RP.

• Authors: Taku Ozaki, Sei-ichi Ishiguro, Satoshi Hirano, Ayaka Baba, Tetsuro Yamashita, Hiroshi Tomita, Mitsuru Nakazawa
• Journal: PloS one (PLoS One) Vol. 8 Issue 8 Pg. e71650 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23951212 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Inducing Factor
• Mitochondrial Proteins
• Ophthalmic Solutions
• Pdcd8 protein, mouse
• Peptides
• Rhodopsin
• Calpain
• mu-calpain

Topics

• Animals
• Apoptosis Inducing Factor (antagonists & inhibitors, genetics, metabolism)
• Calpain (antagonists & inhibitors, genetics, metabolism)
• Cell Death (drug effects)
• Cell Nucleus (drug effects, metabolism)
• Disease Models, Animal
• Electroretinography
• Gene Expression Regulation
• In Situ Nick-End Labeling
• Intravitreal Injections
• Mitochondria (drug effects, metabolism)
• Mitochondrial Proteins (antagonists & inhibitors, genetics, metabolism)
• Mutation
• Ophthalmic Solutions
• Peptides (chemical synthesis, pharmacology)
• Photoreceptor Cells, Vertebrate (drug effects, metabolism, pathology)
• Protein Transport (drug effects)
• Rats
• Rats, Transgenic
• Retinitis Pigmentosa (drug therapy, genetics, metabolism, pathology)
• Rhodopsin (genetics, metabolism)
• Signal Transduction