Apoptosis in Retinal Degeneration—Recent Developments

doi:10.4236/ojapo.2014.31001

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Open Journal of Apoptosis, 2014, 3, 1-3

Published Online January 2014 (http://www.scirp.org/journal/ojapo)

http://dx.doi.org/10.4236/ojapo.2014.31001

OPEN ACCESS OJApo

Apoptosis in Retinal Degeneration—Recent Developments

Magdalene J. Seiler

Anatomy & Neurobiology, UC Irvine School of Medicine, Irvine, USA

Email: [email protected]

Received August 17, 2013; revised September 25, 2013; accepted October 8, 2013

which permits unrestricted use, distributi on, and reproduction in any medium, provided the original work is properly cited. In accor-

Dear Readers,

Irreversible degeneration of photoreceptors and RPE

cells affects millions of patients in diseases such as age-

related macular degeneration (AMD) and retinitis pig-

mentosa (RP) and is a major cause of disability. Thus,

many researchers investigate the causes of photoreceptor

degeneratio n and how to prevent it. Rod and cone pho to-

receptors are one of the most physiologically active cells

in the body. There are different experimental models of

photoreceptor degeneration: hereditary models, retinal

detachment and environmentally induced retinal degene-

ration, such as exposure to bright or continuous light or

chemical injury. Almost hundred papers are published in

this subject every year. This short review wants to con-

cen- trate on just a few publications.

Using a light damage model of exposure to low conti-

nuous light which results in a 50% r eduction of the outer

nuclear layer after 7 d, Contin et al. showed rod photo-

receptor cell death is independent of caspase 3 (as has

been shown by others). Rhodopsin expression did not

decrease before rod death, but rhodopsin became more

phosphorylated at the Ser334 residue after light damage

[1]. Abnormal rhodopsin phosphorylation has also been

reported in rhodopsin mutants [2].

One of the most severe and sudden developing retinal

diseases is neovascular (“wet”) AMD (age-related macu-

lar degeneration) where leaky blood vessels grow into

the subretinal space detaching the photoreceptors from

their supportive retinal pigment epithelium (RPE). No-

tomi and colleagues [3] recently demonstrated that a sig-

nificant increase in extracellular ATP occurs in neovas-

cular AMD with subretinal hemorrhage (bleeding). This

initiates neurodegenerative processes that are specifically

tied to the ligand-gated ion channel 7 of the Purinergic

receptor P2X (P2RX7; P2X7 receptor). Photoreceptor

cell apoptosis is accompanied with activation of caspase-

9 and translocation of apoptosis-inducing factor (AIF)

from mitochondria to nuclei, as well as TUNEL-detect-

able DNA fragmentation. In mouse models (cell culture

of retinal cells exposed to blood and an in vivo model of

subretinal hemorrhage), photoreceptor cell apoptosis was

prevented by a selective P2RX7 antagonist, b rilliant blue

G (BBG), which is an approved adjuvant in ocular sur-

gery [3].

In a retinal detachment model of retinal degeneration,

Zhu et al. showed that photoreceptor apoptosis can be

reduced by RNAi (inhibitor RNA) for GADD153 (grow-

th arrest DNA damage-inducible gene 153, also known

as C/EBP homologous protein) with is involved in en-

doplasmatic reticulum stress during apoptosis and upre-

gulated after retinal detachment [4]. Lentivirus with

GADD153 siRNA was injected 2 weeks before retinal

detachment, and retinas analyzed 1 - 7 days after de-

tachmen t. GADD153 siRNA prevented loss of photore-

ceptors and preserved the outer nuclear layer. The au-

thors suggested the gene therapy with GADD153 siRNA

may be effective in retinal diseases. However, it needs to

be emphasized that the treatment was done 2 weeks be-

fore the injury, similar to the effect of various growth

factors that prevent retinal degeneration after light dam-

age.

In retinitis pigmentosa, mutations in rod proteins lead

to apoptosis of rod photoreceptors which then triggers

later “non-autonomous” cone death. This has the greatest

impact on human vision because cones provide daylight,

high acuity color vision. If cone death could be prevented

in retinitis pigmentosa, the patients would still have use-

ful daylight vision.

Cone death after rod apoptosis (as is common in reti-

nitis pigmentosa) can be delayed by insulin treatment and

the Insulin receptor (IR)-phosphoinositide 3-kinase

(PI3K) signaling pathway, indicating that cones surviv-

ing after rod death are starving [5]. Conditional deletion

of the p85α subunit of the phosphoinositide 3-kinase

(PI3K, a downstream effector of the insulin receptor)

specifically in cone photoreceptors in transgenic mice

M. J. SEILER

OPEN ACCESS OJApo

(using Cre-Lox technology) results in age-related cone

degeneration [6]. These studies suggest that cones may

have their own endogenous PI3K/Insulin-mediated neu-

roprotective pathway in addition to the cone viability

survival s i gnals deri ved from rods [6].

p53, a tumor suppressor protein involved in apoptosis

during development, does not seem to be involved in

photoreceptor apoptosis in the rd mouse, a model of reti-

nitis pigmentosa, as rd mice that have p53 knocked out

show the same rate of degeneration as rd mice with p53

[7]. However, p53 is upregulated when retinal pigment

epithelium (RPE) cells are exposed to bright light and

undergo apoptosis [7]. Thus, cell death mechanisms dif-

fer between photoreceptors and RPE. In a follow up pa-

per [8], the same authors demonstrate that p53 is in-

volved in developmental cell death, as a transgenic

mouse over-expressing p53 (“super p53” mice) showed

loss of rods and inner retinal cells combined with reduc-

tion of function of both rods and cones, but no age-de-

pendent progression of photoreceptor death due to in-

creased apoptosis during retinal development. In contrast,

transgenic mice that specifically expressed p53 specifi-

cally in photoreceptors (“HIP mice”) showed progressive

cells dea t h o f b oth rods and c ones.

Partial reprogramming of adult rods to cones by

knockout of Nrl (neural retinal leucine zipper gene, es-

sential for rod photoreceptors) results in protection of

cone function and retinal integrity in two RP models, rd1

and rho−/− mice that have mutations in rod phototrans-

duction proteins [9]. The investigators achieved this re-

programming by creating transgenic mice with an Nrl

flowed allele (that developed a normal retina), and then

crossing the Nrl floxed mouse to a transgenic line carry-

ing a tamoxifen-inducible Cre recombinase, so they

could induce Nrl knockout by taxominofen treatment in

adult mice. However, in adult mice, rods could only par-

tially be reprogrammed to cones bu t this was suff icient to

prevent cone death and to maintain cone function.

On the other hand, mutations in cone phototransduc-

tion proteins only lead to apoptosis of cones without af-

fecting rods. However, Cho et al. [10] showed recently

cone-dependent rod death after conditional ablation of

Ran-binding protein-2 (Ranbp2) in cone photoreceptors

in mice. (Ranbp2 is essential for viability and energy

metabolism, and plays a critical role cell-type dependent

role in mediating gene-environment interactions. Muta-

tions or deficits in Ranbp2 have been implicated in a

variety of diseases, such as Parkinson, light toxicity, and

the effects of carcinogens.) Cone-specific ablation of

Ranbp2 causes non-apoptotic cone death, followed by

death of rods. Dying rod populations were mixed apop-

totic (TUNEL, Caspase 3) and necrotic (cell plasma per-

meability by EthD-III). These data support the existence

of complex, unique and atypical cell death mechanisms

between rod and cone photoreceptors which are likely

determined by the cell-type dependent activities of

Ranbp2.

In summary, photoreceptor apoptosis often does not

follow the classical apoptotic pathways.

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M. J. SEILER

OPEN ACCESS OJApo

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