Open Journal of Apoptosis, 2014, 3, 1-3
Published Online January 2014 (
Apoptosis in Retinal Degeneration—Recent Developments
Magdalene J. Seiler
Anatomy & Neurobiology, UC Irvine School of Medicine, Irvine, USA
Received August 17, 2013; revised September 25, 2013; accepted October 8, 2013
Copyright © 2014 Magdalene J. Seiler. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distributi on, and reproduction in any medium, provided the original work is properly cited. In accor-
dance of the Creative Commons Attribution License all Copyrights © 2014 are reserved for SCIRP and the owner of the intellectual
property Magdalene J. Seiler. All Copyright © 2014 are guarded by law and by SCIRP as a guardian.
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-
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
(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
In summary, photoreceptor apoptosis often does not
follow the classical apoptotic pathways.
[1] M. A. Contin, M. M. Arietti, M. M. Benedetto, C. Bussi
and M. E. Guido, “Photoreceptor Damage Induced by
Low-Intensity Light: Model of Retinal Degeneration in
Mammals,” Molecular Vision, Vol. 19, No. , 2013, pp.
[2] Y. Saito, H. Ohguro, I. Ohguro, N. Sato, F. Ishikawa, H.
Yamazaki, T. Metoki, T. Ito and M. Nakazawa, “Misre-
gulation of Rhodopsin Phosphorylation and Dephospho-
rylation Found in P23H Rat Retinal Degeneration,” Clin-
ical Ophthalmology, Vol. 2, No. 4, 2008, pp. 821-828.
[3] S. Notomi, T. Hisatomi, Y. Murakami, H. Terasaki, S.
Sonoda, R. Asato, A. Takeda, Y. Ikeda, H. Enaida, T.
Sakamoto and T. Ishibashi, Dynami c Increase in Extra-
cellular ATP Accelerates Photoreceptor Cell Apoptosis
via Ligation of P2RX7 in Subretinal Hemorrhage,” PLoS
ONE, Vol. 8, No. 1, 2013, Ar ticle ID: e53338.
[4] H. Zhu, J. Qian, W. Wang, Q. Yan, Y. Xu, Y. Jiang, L.
Zhang, F. Lu, W. Hu, X. Zhang, F. Wang and X. Sun,
“RNA Interference of GADD153 Protects Photoreceptors
from Endoplasmic Reticulum Stress-Mediated Apoptosis
after Retinal Detachment,” PLoS ONE, Vol. 8, No. 3,
2013, Article ID: e59339.
[5] C. Punzo, K. Kornacker and C. L. Cepko, Stimulation of
the Insulin/mTOR Pathway Delays Cone Death in a
Mouse Model of Retinitis Pigmentosa,” Nature Neuro-
science, Vol. 12, No. 1, 2009, pp. 44-52.
[6] A. Rajala, R. Dighe, M. P. Agbaga, R. E. Anderson and R.
V. Rajala, “Insulin Receptor Signaling in Cones,” The
Journal of Biological Chemistry, Vol. 288, No. 27, 2013,
pp. 19503-19515.
[7] L. Vuong, S. M. Conley and M. R. Al-Ubaidi, “Expres-
sion and Role of p53 in the Retina,” Investigative Oph-
thalmology & Visual Science, Vol. 53, No. 3, 2012, pp.
[8] L. Vuong, D. E. Brobst, I. Ivanovic, D. M. Sherry and M.
R. Al-Ubaidi, “p53 Selectively Regulates Developmental
Apoptosis of Rod Photoreceptors,PLoS ONE, Vol. 8,
No. 6, 2013, Article ID: e67381.
[9] C. L. Montana, A. V. Kolesnikov, S. Q. Shen, C. A. My-
ers, V. J. Kefalov and J. C. Corbo, Reprogramming of
Adult Rod Photoreceptors Prevents Retinal Degeneration,”
Proceedings of the National Academy of Sciences of the
United States of America, Vol. 110, No. 5, 2013, pp.
[10] K. I. Cho, M. Haque, J. Wang, M. Yu, Y. Hao, S. Qiu, I.
C. Pillai, N. S. Peachey and P. A. Ferreira, Distinct and
Atypical Intrinsic and Extrinsic Cell Death Pathways be-
tween Photoreceptor Cell Types upon Specific Ablation
of Ranbp2 in Cone Photoreceptors,” PLOS Genetics, Vol.
9, No. 6, 2013, Article ID: e1003555.