Apoptosis, retinitis pigmentosa, and degeneration

The mechanism of photoreceptor cell death in different inherited retinal degenerations is not fully understood. Mutations in a number of different genes (such as rhodopsin, the beta subunit of cGMP phosphodiesterase, and peripherin) have been identified as the primary genetic lesion in different forms of human retinitis pigmentosa, one of the most common causes of inherited blindness. In all cases the manifestation of the disorder regardless of the specific primary genetic lesion is similar, resulting in photoreceptor cell degeneration and blindness. A recent hypothesis is that the active photoreceptor cell death, which is characteristic of these genetically distinct disorders, is mediated by a common induction of apoptosis. In the present review, the current evidence for active cell death during retinal cell death in several different rodent models of retinitis pigmentosa and retinal degeneration is examined.Key words: retinal degeneration, apoptosis, retinitis pigmentosa, clusterin, DNA fragmentation.

Download Full-text

A rat model for retinitis pigmentosa with rapid retinal degeneration enables drug evaluation in vivo

Biological Procedures Online ◽

10.1186/s12575-021-00150-y ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Chisato Inoue ◽

Tamaki Takeuchi ◽

Akira Shiota ◽

Mineo Kondo ◽

Yuji Nshizawa

Keyword(s):

Retinitis Pigmentosa ◽

Retinal Degeneration ◽

Rat Model ◽

Photoreceptor Cell ◽

Photoreceptor Cells ◽

Therapeutic Agents ◽

Transgenic Rat ◽

Cell Degeneration ◽

Rat Strain

Abstract Background Although retinitis pigmentosa (RP) is most frequently studied in mouse models, rats, rabbits, and pigs are also used as animal models of RP. However, no studies have reported postnatal photoreceptor cell loss before complete development in these models. Here, we generated a transgenic rat strain, named the P347L rat, in which proline at position 347 in the rhodopsin protein was replaced with leucine. Results A pathological analysis of photoreceptor cells in the P347L rat model was performed, and drugs with potential use as therapeutic agents against RP were investigated. The data clearly showed rapid degeneration and elimination of the outer nuclear layer even before the photoreceptor cells were fully established in P347L rats. To test the usefulness of the P347L rat in the search for new therapeutic agents against RP, the effects of rapamycin on RP were investigated in this rat strain. The findings suggest that rapamycin promotes autophagy and autophagosomal uptake of the rhodopsin that has accumulated abnormally in the cytoplasm, thereby alleviating stress and delaying photoreceptor cell death. Conclusions In this RP model, the time to onset of retinal degeneration was less than that of previously reported RP models with other rhodopsin mutations, enabling quicker in vivo evaluation of drug efficacy. Administration of rapamycin delayed the photoreceptor cell degeneration by approximately 1 day.

Download Full-text

Techniques to Quantify cGMP Dysregulation as a Common Pathway Associated with Photoreceptor Cell Death in Retinitis Pigmentosa

Retinal Degenerative Diseases - Advances in Experimental Medicine and Biology ◽

10.1007/978-3-030-27378-1_67 ◽

2019 ◽

pp. 407-411

Author(s):

Paul Yang ◽

Rachel A. Lockard ◽

Hope Titus

Keyword(s):

Cell Death ◽

Retinitis Pigmentosa ◽

Photoreceptor Cell ◽

Common Pathway

Download Full-text

Redefining the role of Ca2+-permeable channels in photoreceptor degeneration using diltiazem

Cell Death and Disease ◽

10.1038/s41419-021-04482-1 ◽

2022 ◽

Vol 13 (1) ◽

Author(s):

Soumyaparna Das ◽

Valerie Popp ◽

Michael Power ◽

Kathrin Groeneveld ◽

Jie Yan ◽

...

Keyword(s):

Cell Death ◽

Retinal Degeneration ◽

Photoreceptor Cell ◽

Strong Increase ◽

Channel Blockers ◽

Photoreceptor Degeneration ◽

Therapy Development ◽

Hypertensive Drug ◽

Future Therapy

AbstractHereditary degeneration of photoreceptors has been linked to over-activation of Ca2+-permeable channels, excessive Ca2+-influx, and downstream activation of Ca2+-dependent calpain-type proteases. Unfortunately, after more than 20 years of pertinent research, unequivocal evidence proving significant and reproducible photoreceptor protection with Ca2+-channel blockers is still lacking. Here, we show that both D- and L-cis enantiomers of the anti-hypertensive drug diltiazem were very effective at blocking photoreceptor Ca2+-influx, most probably by blocking the pore of Ca2+-permeable channels. Yet, unexpectedly, this block neither reduced the activity of calpain-type proteases, nor did it result in photoreceptor protection. Remarkably, application of the L-cis enantiomer of diltiazem even led to a strong increase in photoreceptor cell death. These findings shed doubt on the previously proposed links between Ca2+ and retinal degeneration and are highly relevant for future therapy development as they may serve to refocus research efforts towards alternative, Ca2+-independent degenerative mechanisms.

Download Full-text

Minocycline decreases CCR2-positive monocytes in the retina and ameliorates photoreceptor degeneration in a mouse model of retinitis pigmentosa

PLoS ONE ◽

10.1371/journal.pone.0239108 ◽

2021 ◽

Vol 16 (4) ◽

pp. e0239108

Author(s):

Ryo Terauchi ◽

Hideo Kohno ◽

Sumiko Watanabe ◽

Saburo Saito ◽

Akira Watanabe ◽

...

Keyword(s):

Cell Death ◽

Retinal Degeneration ◽

Photoreceptor Cell ◽

Fluorescent Protein ◽

Outer Nuclear Layer ◽

Inhibitory Effect ◽

Subretinal Space ◽

Photoreceptor Degeneration ◽

Retinal Inflammation ◽

Green Fluorescent

Retinal inflammation accelerates photoreceptor cell death caused by retinal degeneration. Minocycline, a semisynthetic broad-spectrum tetracycline antibiotic, has been previously reported to rescue photoreceptor cell death in retinal degeneration. We examined the effect of minocycline on retinal photoreceptor degeneration using c-mer proto-oncogene tyrosine kinase (Mertk)−/−Cx3cr1GFP/+Ccr2RFP/+ mice, which enabled the observation of CX3CR1-green fluorescent protein (GFP)- and CCR2-red fluorescent protein (RFP)-positive macrophages by fluorescence. Retinas of Mertk−/−Cx3cr1GFP/+Ccr2RFP/+ mice showed photoreceptor degeneration and accumulation of GFP- and RFP-positive macrophages in the outer retina and subretinal space at 6 weeks of age. Mertk−/−Cx3cr1GFP/+Ccr2RFP/+ mice were intraperitoneally administered minocycline. The number of CCR2-RFP positive cells significantly decreased after minocycline treatment. Furthermore, minocycline administration resulted in partial reversal of the thinning of the outer nuclear layer and decreased the number of apoptotic cells, as assessed by the TUNEL assay, in Mertk−/−Cx3cr1GFP/+Ccr2RFP/+ mice. In conclusion, we found that minocycline ameliorated photoreceptor cell death in an inherited photoreceptor degeneration model due to Mertk gene deficiency and has an inhibitory effect on CCR2 positive macrophages, which is likely to be a neuroprotective mechanism of minocycline.

Download Full-text