Molecular mechanisms of light-induced photoreceptor apoptosis and neuroprotection for retinal degeneration

https://doi.org/10.1016/j.preteyeres.2004.08.002Get rights and content

Abstract

Human retinal dystrophies and degenerations and light-induced retinal degenerations in animal models are sharing an important feature: visual cell death by apoptosis. Studying apoptosis may thus provide an important handle to understand mechanisms of cell death and to develop potential rescue strategies for blinding retinal diseases. Apoptosis is the regulated elimination of individual cells and constitutes an almost universal principle in developmental histogenesis and organogenesis and in the maintenance of tissue homeostasis in mature organs.

Here we present an overview on molecular and cellular mechanisms of apoptosis and summarize recent developments. The classical concept of apoptosis being initiated and executed by endopeptidases that cleave proteins at aspartate residues (Caspases) can no longer be held in its strict sense. There is an increasing number of caspase-independent pathways, involving apoptosis inducing factor, endonuclease G, poly-(ADP-ribose) polymerase-1, proteasomes, lysosomes and others. Similarly, a considerable number and diversity of pro-apoptotic stimuli is being explored.

We focus on apoptosis pathways in our model: light-damage induced by short exposures to bright white light and highlight those essential conditions known so far in the apoptotic death cascade. In our model, the visual pigment rhodopsin is the essential mediator of the initial death signal. The rate of rhodopsin regeneration defines damage threshold in different strains of mice. This rate depends on the level of the pigment epithelial protein RPE65, which in turn depends on the amino acid (leucine or methionine) encoded at position 450. Activation of the pro-apoptotic transcription factor AP-1 constitutes an essential death signal. Inhibition of rhodopsin regeneration as well as suppression of AP-1 confers complete protection in our system.

Furthermore, we describe observations in other light-damage systems as well as characteristics of animal models for RP with particular emphasis on rescue strategies. There is a vast array of different neuroprotective cytokines that are applied in light-damage and RP animal models and show diverging efficacy. Some cytokines protect against light damage as well as against RP in animal models. At present, the mechanisms of neuroprotective/anti-apoptotic action represent a “black box” which needs to be explored.

Even though acute light damage and RP animal models show different characteristics in many respects, we hope to gain insights into apoptotic mechanisms for both conditions by studying light damage and comparing results with those obtained in animal models.

In our view, future directions may include the investigation of different apoptotic pathways in light damage (and inherited animal models). Emphasis should also be placed on mechanisms of removal of dead cells in apoptosis, which appears to be more important than initially recognized. In this context, a stimulating concept concerns age-related macular degeneration, where an insufficiency of macrophages removing debris that results from cell death and photoreceptor turnover might be an important pathogenetic event. In acute light damage, the appearance of macrophages as well as phagocytosis by the retinal pigment epithelium are a consistent and conspicuous feature, which lends itself to the study of removal of cellular debris in apoptosis.

We are aware of the many excellent reviews and the earlier work paving the way to our current knowledge and understanding of retinal degeneration, photoreceptor apoptosis and neuroprotection. However, we limited this review mainly to work published in the last 7–8 years and we apologize to all the researchers which have contributed to the field but are not cited here.

Introduction

Retinal dystrophies termed RP comprise a large, heterogeneous group of inherited diseases that often lead to blindness. Main symptoms include progressive loss of visual functions with night blindness, narrowing of the visual field, reduced central vision and increasing sensitivity to glare. The mode of inheritance may be autosomal-dominant, autosomal-recessive, x-chromosal and mitochondrial. So called simplex cases mostly are transmitted by autosomal-recessive or x-chromosomal inheritance with no other affected family members known, spontaneous mutations are rare. Disease prevalence is about 0.3‰ (Bird, 1995; Kellner et al., 2004).

By contrast, AMD shows a high prevalence with a distinct trend of increase: about 10–20% of people over the age of 65 suffer from maculopathy (an early stage) or overt macular degeneration. This figure is thought to increase during the next decades notably independent of an increase of the elderly population, according to epidemiological extrapolations (Bok, 2002). In the US, about 1.75 million people suffer from AMD, this number will increase to about 3 million in 2020 (Friedman et al., 2004). While the pathogenesis of AMD is likely to result from several interacting components such as mutations in potential causative and susceptibility genes, metabolic stress on the RPE and adjacent tissues and exogenous factors (Silvestri, 1997; Hayward et al., 2003; Tomany et al., 2004), other forms of macular disease are inherited, like Stargardt's or Best's disease, Sorsby's fundus dystrophy or cone dystrophies (Kellner et al., 2004).

By now it is almost a classical statement that apoptosis of photoreceptors (and the RPE) is the final cell death pathway in RP and in AMD (Chang et al., 1993; Portera-Cailliau et al., 1994a).

While the apoptotic end stage is well-documented in animal models and in human autopsy eyes, there is a large gap between knowledge of gene mutations (see, for example, RetNet at http://www.sph.uth.tmc.edu/Retnet/disease.htm) on the one hand and events on the cellular and molecular levels leading to cell death including signaling and death pathways on the other hand. Why can cells bearing a gene mutation or cells being exposed to lifelong metabolic and/or environmental stress survive for extended periods of time despite having the death promoting stimulus present? Which pathogenic factors eventually trigger the “decision” to die? Why is cell death protracted in most instances even though genetic or other stress on physiological cell function is present for a long time and, presumably, equally in all cells?

In the case of RP, mutations in different genes and different mutations in the same gene can result in similar phenotypes; however, different phenotypes may also be caused by the same mutation. Maculopathy and “physiological” ageing of the retina may remain without severe visual disturbances while in patients, disease with loss of central vision is developing from those stages. Molecular components of drusen can differ in AMD—eyes and healthy age—matched controls (Crabb et al., 2002; Dentchev et al., 2003) thus offering potential clues to the pathogenesis.

This inherent complexity of both RP and AMD aggravates the elucidation of death mechanisms and along with that of possible therapies. For research in RP there is by now a multitude of animal models available reflecting the human disease, but animal models are rare for AMD. Only recently a mouse model was described which showed several morphological features typical for AMD including apoptotic cell death (Ambati et al., 2003).

Several strategies to preserve visual functions are developed in animal models. They comprise transplantation of stem cells, RPE or retinal sheaths, delivery of a large number of neuroprotective cytokines, gene therapy including replacement of missing proteins or removal of harmful molecules (Vision research conference, 2003; Bird, 2004), implantation of subretinal or epiretinal chips or cortically based electrodes (Eckmiller, 1997; Zrenner, 2001; Alteheld et al., 2004). At present, neuroprotection and certain gene-therapies appear to be among the most promising approaches. Because apoptosis is the final pathway of cell removal, prevention of apoptosis is conceptually feasible for all types of mutations and for AMD. This is in contrast to the gene therapy where genetic screening for each patient needs to be performed before a therapy strategy can be envisioned. Similarly, other therapeutic interventions meet various obstacles in practice. Therefore the inhibition of apoptosis as the downstream final event appears to be a logical approach. However, successful prevention of apoptosis will require, at least in part, the understanding of signaling and death mechanisms. The protracted cell death in most animal models (and humans) renders the study of apoptotic mechanisms rather difficult due to scarcity of material. Only few animal models have a short period of accumulated cell death that might provide a fair amount of material to study and a time frame for experimental manipulations. However, this disease-induced cell death can coincide with histogenetic, developmental cell death, such as in the rd1 mouse, a condition that could mask the mechanisms of degenerative apoptosis.

The above considerations led us to develop a model system that permits to investigate a synchronized burst of apoptosis, thus enabling the analysis of various parameters in the same group of animals.

In recent years it became clear that there is no defined and limited set of apoptotic mechanisms in general. Instead, there is a vast multitude of stimuli and initiation steps leading to the execution of cell death and the removal of dead cells, were the two processes appear to converge to fewer and thus more general mechanisms. This diversity found in non-ocular tissues may be true for the retina as well.

Despite its limitations, namely, an artificial induction of apoptosis by an exogenous stimulus, which is not inherently present within the cell as a death signal, our model of light-induced apoptosis permits to study physiological and pathological events in photoreceptor apoptosis. However, they may not all be extrapolated from one experimental system to another, that is, to models of retinal dystrophies and degenerations. Therefore, this review will focus on cellular and molecular events of light-induced apoptosis with some comparisons to inherited degenerations. We will mainly discuss the light regimen that leads to cell death in our system: short-term exposure to bright white fluorescent light.

Both development and maintenance of an organism depend not only on cell proliferation but also on the controlled induction and execution of cell death. PCD is one of the most important principals to ensure the correct maturation and function of organs. In the adult organism, a fine-tuned balance between cell proliferation and cell death is required to maintain tissue homeostasis and to remove cells with functional or structural deficits, which otherwise might affect the whole organ and eventually endanger the viability of the entire organism. This form of cell death is usually referred to as apoptosis. However, if gene mutations or exogenous stimuli above threshold are present, apoptotic cell death may drastically affect proper function of organs and as such, apoptosis is involved in many neurodegenerative diseases like Alzheimer or Parkinson's disease (Mattson, 2000). In the retina, apoptosis plays a major role in the loss of visual cells in blinding disorders like RP (van Soest et al., 1999) or AMD (Dunaief et al., 2002).

Morphological characteristics of apoptosis have first been described by Kerr and coworkers (Kerr et al., 1972) and involve condensation of chromatin, membrane blebbing and disintegration of dying cells into apoptotic bodies, which are engulfed by phagocytic cells. Prominent physiological alterations during apoptosis include internucleosomal DNA cleavage (Nagata, 2000) and exposure of phosphatidylserine to the outside of cellular membranes (Schlegel and Williamson, 2001). Classically, endopeptidases that cleave proteins at aspartate residues (Caspases) were considered central executioners of the apoptotic program cleaving a variety of intracellular substrates. A simplistic view argued that most if not all apoptotic events involve caspases and converge at some point to a common death pathway leading to the ‘quiet removal’ of surplus cells during development and of injured/defective cells in adult tissues. However, this view had to be changed dramatically in recent years when researchers discovered not only a multitude of caspase-independent apoptotic pathways (see below) but also when it became clear that apoptosis might involve various cellular compartments like mitochondria, lysosomes, proteasomes or autophagic vacuoles. Even the long-standing and straightforward distinction between apoptosis and necrosis was challenged with the recognition that lysosomal and cellular proteases including caspases may be involved in both types of cell death (Syntichaki and Tavernarakis, 2003). Furthermore, some dying cells show morphological features of both apoptosis and necrosis (Sperandio et al., 2000; Wyllie and Golstein, 2001), the same stimulus can induce apoptosis and necrosis (Vercammen et al., 1998) and phagocytosis of apoptotic bodies and of necrotic cells both involve recognition of externalized phosphatidylserine (Brouckaert et al., 2004). It is also noteworthy that positive TUNEL-staining, which initially was thought to specifically demonstrate apoptotic cells, may also occur in case of DNA single-strand breaks in necrotic cells.

In many systems, apoptotic cell death invariably involves the activation of caspases that cleave over 100 known substrates on the carboxyl side of aspartate residues (Earnshaw et al., 1999; Kaufmann and Hengartner, 2001). Caspases have been classified into two major groups: Caspases-1, -4, -5, -11, -12 and -14 seem to participate in cytokine cleavage and maturation, whereas caspases-2, -3, -6, -7, -8, -9 and -10 are directly involved in apoptosis by cleaving various intracellular proteins (Strasser et al., 2000; Kaufmann and Hengartner, 2001). All caspases are produced as zymogens containing an N-terminal prodomain as well as a large and a small subunit. Upon cleavage by a caspase-dependent process, large and small subunits are released and form the mature caspase in a α2β2 configuration with 2 large and 2 small subunits (Kaufmann and Hengartner, 2001).

Two major pathways have been described for caspase activation. The first one is initiated by extracellular ligands that bind to death receptors like the Fas/CD95 or TNFα receptor. The DDs of these receptors recruit adaptor molecules like FADD or RAIDD, which in turn may interact with procaspase-8 leading either directly to the activation of a cleavage cascade culminating in the maturation of effector caspases such as caspase-3 or to the cleavage of Bid, a member of the Bcl-2 family of proteins (Budihardjo et al., 1999). Bid cleavage releases a truncated fragment which facilitates the release of cytochrome c from mitochondria, thereby converging with the second pathway of caspase activation described below (Kaufmann and Hengartner, 2001).

The second pathway (also known as the intrinsic pathway) to caspase activation induces the release of cytochrome c (Green and Reed, 1998) and of other polypeptides like Smac/Diablo and HtrA2/Omi from mitochondria without the involvement of death receptors (Du et al., 2000; Verhagen et al., 2000; Suzuki et al., 2001). Instead, proteolytic cleavage of Bid by Granzyme B (Barry et al., 2000; Heibein et al., 2000) and/or by some lysosomal cathepsins (Stoka et al., 2001) may initiate the mitochondrial pathway from within the cell. Yet other stimuli like DNA damage can induce cytochrome c release without Bid cleavage (Kaufmann and Hengartner, 2001). The release of the polypeptides from mitochondria facilitates activation of downstream effector caspases either by activating Apaf-1 (Li et al., 1997) or by interacting with and inhibiting members of the IAP protein family (Liu et al., 2000; Martins et al., 2002). However, HtrA2/Omi can also contribute to caspase-independent cell death processes through an intrinsic serine protease activity (Suzuki et al., 2001). Released cytochrome c facilitates the assembly of Apaf-1 with procaspase-9 into a structure called the apoptosome which can proteolytically process procaspase-3 (Adrain and Martin, 2001) leading to full activation of the apoptotic process.

Apoptosis in general depends on proteolytic degradation of proteins involved in a number of cellular functions. A steadily increasing number of systems shows that cleavage of proteins during apoptosis does not necessarily need to involve caspases. Non-caspase proteases linked to apoptotic cell death include cathepsins, calpains, granzymes A and B, serine proteases like AP24 and proteasomes (Wright et al., 1994; Johnson, 2000; Altairac et al., 2003; Friedman and Xue, 2004). Most, if not all of these enzymes can act together with, or independent of caspases as executioners of apoptosis. In addition, mitochondrial membrane permeabilization may be induced in a caspase-independent manner releasing caspase-independent death effectors such as AIF (Susin et al., 1999) or EndoG (Li et al., 2001; van Loo et al., 2001).

AIF is a conserved oxidoreductase normally localized in mitochondria (Miramar et al., 2001). Reduced AIF activity leads to a reduced tolerance to oxidative stress suggesting that AIF has an important physiological function in the regulation of oxidative processes (Klein et al., 2002). Like cytochrome c, AIF has a dual role in life and death of a cell (Cregan et al., 2004). Upon activation by appropriate stimuli, AIF is released from mitochondria and translocates to the nucleus where it actively participates in the execution of the cell. AIF may induce cell death by triggering chromatin condensation and cleavage of DNA into fragments of 50 kb and larger (Susin et al., 1999). However, since AIF cannot cleave DNA on its own (Susin et al., 1999), it is believed that AIF recruits or activates endonucleases upon entry in the nucleus (Ye et al., 2002).

One of these endonucleases may have been identified in EndoG, which, like AIF, is normally localized to mitochondria. Upon apoptotic stimuli, however, EndoG may translocate to the nucleus (Lemarie et al., 2004). Experiments in DFF45/ICAD knockout animals showed that EndoG can induce DNA cleavage in the complete absence of DFF45/ICAD, the key caspase-dependent DNA fragmentation factor (Li et al., 2001). This suggests that EndoG is a truly caspase-independent DNA cleavage factor capable of inducing the apoptotic pathway on its own. In C. elegans EndoG seems to form a ‘degradosome’ through an interaction with WAH1 (the C. elegans homolog of AIF) and with other downstream nucleases (Parrish et al., 2003; Cregan et al., 2004). In vitro studies showed that co-incubation of EndoG with WAH-1 strongly induces the otherwise low nuclease activity of EndoG (Wang et al., 2002) suggesting that the formation of the nuclear ‘degradosome’ enhances DNA fragmentation and apoptotic cell death. Evidence for a mammalian ‘degradosome’ is lacking so far and studies suggest that AIF and EndoG can induce nuclear chromatin breakdown in mammalian nuclei independently from one another (Susin et al., 1999; Li et al., 2001). However, it seems likely that also in mammalian cells AIF interacting proteins may exist that participate in or even facilitate cleavage of nuclear chromatin.

An important role in the process of caspase-independent cell death has recently been assigned to PARP-1 which has been described as a ‘guardian of the genome’ under physiological conditions as PARP-1 is involved in DNA repair by sensing DNA strand breaks (Jeggo, 1998; Chatterjee et al., 1999). Upon activation, PARP-1 metabolizes β-nicotinamide adenine dinucleotide and forms polymers of ADP-ribose which are then transferred to a number of enzymes and proteins in the nucleus including DNA polymerases, endonucleases, chromatin-binding proteins and histones (Chiarugi, 2002). PARP-1 action may facilitate the repair of the genomic DNA by opening the condensed chromatin structure. If over-stimulated (e.g. by excessive oxidant-induced DNA damage), PARP-1 can induce cell death through NAD+ consumption and energy depletion of the cell. Pharmacological inhibition of PARP-1 activity or deletion of the PARP-1 gene leads to a strong protection against tissue damage in diverse conditions such as cerebral ischemia, myocardial infarction and streptozotoxin-induced diabetes (Pieper et al., 1999). In a recent study, Yu and colleagues identified AIF as a key molecule in PARP-1 mediated, caspase-independent cell death (Yu et al., 2002). MNNG induces cell death involving DNA alkylation, mitochondrial membrane depolarization, release of cytochrome c and nuclear translocation of AIF. PARP-1 deficient cells did not induce AIF translocation and were completely protected against MNNG-mediated cell death. Similarly, inhibition of nuclear translocation of AIF in wild-type cells protected against cell death. NMDA treatment induces nuclear translocation of AIF preceeding cell death in neurons. PARP-1 gene ablation or pharmacological inhibition of PARP-1 activity prevented AIF translocation and NMDA-induced cell death (Yu et al., 2002). At least in these models, PARP-1-mediated cell death therefore depends on nuclear translocation of AIF. Since inhibitors of caspase function did not prevent AIF translocation or cell death, PARP-1 and AIF-ruled cell destruction is caspase independent (Yu et al., 2002). Of note is the fact that PARP-1 is a major substrate for cleavage in caspase-dependent cell death. Cleavage of PARP-1 prevents activity of the enzyme in response to DNA damage and may secure large enough energy pools in the cells to allow the orderly cascade of events to occur in this type of apoptotic cell death.

Accumulating evidence suggests that mechanisms of cellular suicide do not only involve isolated apoptotic pathways, whether or not they are dependent on caspases. A well-known and ubiquitous phenomenon is the ‘self-eating’ process of cells (autophagy) that may result in cell death if over stimulated. Autophagy is a major mechanism for the degradation of cytoplasmic organelles. In yeast, autophagy is induced under conditions of stress like nutrient starvation (Abeliovich and Klionsky, 2001) and seems to secure a sufficient supply of amino acids and macromolecules for survival under such harsh conditions. Mammalian cells may also use autophagy to ‘recycle’ or remove cellular constituents in times of special need (Mizushima et al., 2002).

Autophagy starts with the concealment of cytoplasmic material within double-membranes to form the autophagosome. After fusion with lysosomes, autophagosomes become autolysosomes or autophagic vacuoles. Lysosomal enzymes, especially cathepsins (aspartyl- and cysteine proteases) then trigger the final destruction of the engulfed cytoplasmic material.

The process of autophagy is highly regulated and involves various enzymes like kinases, phosphatases, GTPases and others. The concealment of the material targeted for degradation, for example, involves the protein-conjugating enzyme APG10 and the activity of APG7, which is homologous to the E1 family of ubiquitin-activating enzymes required for the degradation of proteins by proteasomes (see below) (Kim et al., 1999; Shintani et al., 1999; Tanida et al., 1999; Klionsky and Emr, 2000).

More than 20 additional genes have been identified in yeast that are involved in autophagy (Klionsky and Emr, 2000). Orthologs of many of these genes have been found in mammalian cells suggesting a strong conservation of the autophagic system (Klionsky and Emr, 2000). One of these genes, Beclin-1, a peripheral membrane protein, is involved in an early step of autophagy and loss of Beclin-1 activity results in reduced formation of autophagic vacuoles (Qu et al., 2003; Yue et al., 2003). Interestingly, Beclin-1 was found to be mono-allelically deleted in many ovarian, breast and prostate cancers and many tumor cell lines express low levels of the protein (Liang et al., 1999; Edinger and Thompson, 2003). Beclin-1 haploinsufficient mice show an increased incidence of spontaneous tumor formation (Qu et al., 2003; Yue et al., 2003). However, the apoptotic response of Beclin-1−/− cells to serum withdrawal or UV light appears normal (Yue et al., 2003). Nevertheless, the hypothesis has been put forward that reduced autophagy (as in Beclin-1 haploinsufficient cells) may lead to reduced cell death and increased cancer formation whereas unrestrained autophagic activity may lead to cell death (Edinger and Thompson, 2003).

Another intracellular proteolytic pathway is represented by the ubiquitin–proteasome system. The sequential action of enzymes E1, E2 and E3 lead to the attachment of ubiquitin moieties to proteins and the subsequent targeting of these polyubiquitinated molecules to degradation in 26S proteasomes which are composed of a 20S core particle and two 19S regulatory particles (Pickart and Cohen, 2004). Not only does the proteasome complex control the levels of many cellular proteins involved in basic processes such as signal transduction and cell cycle control, but also seems to be directly involved in the regulation of apoptosis by mediating the degradation of key pro- and anti-apoptotic regulators such as caspases, Smac/Diablo, XIAP and IAP's (Jesenberger and Jentsch, 2002; Bergmann et al., 2003). The connection of proteasomes with apoptotic cell death is demonstrated not only by the ability of proteasomes to control the levels of apoptotic proteins but also by the regulation of proteasomal activity by caspase-dependent processes. During apoptosis, three subunits of the 19S regulatory particle are cleaved in a caspase-dependent manner probably causing an inactivation of the proteasome and the dissociation of the 20S core particle from the 19S regulatory particles. This may lead to an imbalance of pro- and anti-apoptotic molecules in the cell and to the subsequent induction of apoptotic processes (Friedman and Xue, 2004; Sun et al., 2004).

Apoptosis, autophagy and proteasome activity should therefore not strictly be separated as distinct events. In many settings, these processes are interlinked and may represent the complex reaction of a cell to changes in the environment (Bursch, 2001; Lockshin and Zakeri, 2002; Friedman and Xue, 2004; Gozuacik and Kimchi, 2004).

Section snippets

Studying photoreceptor apoptosis by light damage

Loss of visual cells by apoptosis is a key feature of RP and also of AMD (Portera-Cailliau et al., 1994b) reviewed by Reme et al., 1998a, Reme et al., 2000, Reme et al., 2003a). Thus, understanding the process of photoreceptor apoptosis might provide clues on how to interfere with photoreceptor loss and therefore loss of vision in these diseases. In case of RP, it appears reasonable to assume that the best way to achieve this goal is the use of genetically engineered animal models carrying a

Light damage mechanisms

Light-induced photoreceptor degeneration appears to proceed in separate phases from induction of apoptosis to clearance of the cellular remnants (Fig. 4).

Strategies to interfere with the induction-phase

Induction of photoreceptor apoptosis by light depends on the availability of 11-cis retinal and treatments restricting the availability of this chromophore reduce the sensitivity of photoreceptors for light damage: Halothane blocks rhodopsin regeneration by competing with 11-cis retinal for the binding site in the opsin molecule (Ishizawa et al., 2000). Therefore, halothane prevents the regeneration of rhodopsin after the initial bleach and protects the retina against light damage (Keller et

Possible links between apoptosis and intracellular degradative pathways: proteasomes, lysosomes and autophagy

While in earlier years apoptosis was seen as a process evoked by multiple stimuli on the one hand and by caspases as the main initiators and executioners on the other hand, at present it becomes increasingly clear that also caspase-independent proteolytic processes may play an important role. These include degradative pathways of the ubiquitin–proteasome system, certain lysosomal proteases and lysosome-mediated autophagy (Xue et al., 1999; Jesenberger and Jentsch, 2002; Guicciardi et al., 2004)

Acknowledgements

We gratefully acknowledge the excellent technical assistance of Gaby Hoegger, Cornelia Imsand and Dora Greuter. We would like to thank the Swiss National Science Foundation for continuous support over many years, we thank the German Research Council for important support within the Center Grant Programme “Age Related Macular Degeneration”, the Swiss National Center for Competence in Research, Division Neurodegeneration and Repair, for support. We also thank for generous support: EMDO

References (255)

  • G.Q. Chang et al.

    Apoptosisfinal common pathway of photoreceptor death in rd, rds, and rhodopsin mutant mice

    Neuron

    (1993)
  • A. Chiarugi

    Poly(ADP-ribose) polymerasekiller or conspirator? The ‘suicide hypothesis’ revisited

    Trends Pharmacol. Sci.

    (2002)
  • M. Donovan et al.

    Control of mitochondrial integrity by Bcl-2 family members and caspase-independent cell death

    Biochim. Biophys. Acta

    (2004)
  • M. Donovan et al.

    Light-induced photoreceptor apoptosis in vivo requires neuronal nitric-oxide synthase and guanylate cyclase activity and is caspase-3-independent

    J. Biol. Chem.

    (2001)
  • C. Du et al.

    Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition

    Cell

    (2000)
  • A.L. Edinger et al.

    Defective autophagy leads to cancer

    Cancer Cell

    (2003)
  • J. Friedman et al.

    To live or die by the swordthe regulation of apoptosis by the proteasome

    Dev. Cell

    (2004)
  • E.S. Green et al.

    Two animal models of retinal degeneration are rescued by recombinant adeno-associated virus-mediated production of FGF-5 and FGF-18

    Mol. Ther.

    (2001)
  • F. Hafezi et al.

    Differential DNA binding activities of the transcription factors AP-1 and Oct-1 during light-induced apoptosis of photoreceptors

    Vis. Res.

    (1999)
  • G.S. Hageman et al.

    An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration

    Prog. Retin. Eye Res.

    (2001)
  • T. Harada et al.

    Modification of glial-neuronal cell interactions prevents photoreceptor apoptosis during light-induced retinal degeneration

    Neuron

    (2000)
  • T. Hisatomi et al.

    Clearance of apoptotic photoreceptorselimination of apoptotic debris into the subretinal space and macrophage-mediated phagocytosis via phosphatidylserine receptor and integrin alphavbeta3

    Am. J. Pathol.

    (2003)
  • A.H. Hobson et al.

    Apoptotic photoreceptor death in the rhodopsin knockout mouse in the presence and absence of c-fos

    Exp. Eye Res.

    (2000)
  • H.P. Iseli et al.

    Light damage susceptibility and RPE65 in rats

    Exp. Eye Res.

    (2002)
  • J.H. Jang et al.

    Potentiation of cellular antioxidant capacity by Bcl-2implications for its antiapoptotic function

    Biochem. Pharmacol.

    (2003)
  • H. Abeliovich et al.

    Autophagy in yeastmechanistic insights and physiological function

    Microbiol. Mol. Biol. Rev.

    (2001)
  • P. Ahuja et al.

    Lens epithelium-derived growth factor (LEDGF) delays photoreceptor degeneration in explants of rd/rd mouse retina

    Neuroreport

    (2001)
  • M. Akimoto et al.

    Adenovirally expressed basic fibroblast growth factor rescues photoreceptor cells in RCS rats

    Invest. Ophthalmol. Vis. Sci.

    (1999)
  • S. Altairac et al.

    L-DNase II activation by the 24 kDa apoptotic protease (AP24) in TNFalpha-induced apoptosis

    Cell Death Differ.

    (2003)
  • N. Alteheld et al.

    The retina implant—new approach to a visual prosthesis. A model for intracortical visual prosthesis research

    Biomed. Tech. (Berl)

    (2004)
  • J. Ambati et al.

    An animal model of age-related macular degeneration in senescent Ccl-2- or Ccr-2-deficient mice

    Nat. Med.

    (2003)
  • M. Barry et al.

    Granzyme B short-circuits the need for caspase 8 activity during granule-mediated cytotoxic T-lymphocyte killing by directly cleaving Bid

    Mol. Cell. Biol.

    (2000)
  • J. Bennett et al.

    Adenovirus-mediated delivery of rhodopsin-promoted bcl-2 results in a delay in photoreceptor cell death in the rd/rd mouse

    Gene Ther.

    (1998)
  • A.C. Bird

    What should a clinician know to be prepared for the advent of treatment of retinal dystrophies?

    Novartis Found Symp.

    (2004)
  • C. Bode et al.

    Caspase-3 inhibitor reduces apototic photoreceptor cell death during inherited retinal degeneration in tubby mice

    Mol. Vis.

    (2003)
  • D. Bok

    New insights and new approaches toward the study of age-related macular degeneration

    Proc. Natl. Acad. Sci. USA

    (2002)
  • Brouckaert, G., Kalai, M., Krysko, D.V., Saelens, X., Vercammen, D., Ndlovu, M., Haegeman, G., D’Herde, K.,...
  • I. Budihardjo et al.

    Biochemical pathways of caspase activation during apoptosis

    Annu. Rev. Cell Dev. Biol.

    (1999)
  • W. Bursch

    The autophagosomal–lysosomal compartment in programmed cell death

    Cell Death Differ.

    (2001)
  • R.A. Bush et al.

    The effect of calcium channel blocker diltiazem on photoreceptor degeneration in the rhodopsin Pro213His rat

    Invest. Ophthalmol. Vis. Sci.

    (2000)
  • A.R. Caffe et al.

    A combination of CNTF and BDNF rescues rd photoreceptors but changes rod differentiation in the presence of RPE in retinal explants

    Invest. Ophthalmol. Vis. Sci.

    (2001)
  • P.D. Calvert et al.

    Phototransduction in transgenic mice after targeted deletion of the rod transducin alpha-subunit

    Proc. Natl. Acad. Sci. USA

    (2000)
  • W. Cao et al.

    In vivo protection of photoreceptors from light damage by pigment epithelium-derived factor

    Invest. Ophthalmol. Vis. Sci.

    (2001)
  • R.J. Casson et al.

    The effect of ischemic preconditioning on light-induced photoreceptor injury

    Invest. Ophthalmol. Vis. Sci.

    (2003)
  • R.J. Casson et al.

    The effect of retinal ganglion cell injury on light-induced photoreceptor degeneration

    Invest. Ophthalmol. Vis. Sci.

    (2004)
  • M. Cayouette et al.

    Intraocular gene transfer of ciliary neurotrophic factor prevents death and increases responsiveness of rod photoreceptors in the retinal degeneration slow mouse

    J. Neurosci.

    (1998)
  • S. Chatterjee et al.

    Poly(ADP-ribose) polymerasea guardian of the genome that facilitates DNA repair by protecting against DNA recombination

    Mol. Cell Biochem.

    (1999)
  • E. Chaum

    Retinal neuroprotection by growth factorsa mechanistic perspective

    J. Cell Biochem.

    (2003)
  • J. Chen et al.

    bcl-2 overexpression reduces apoptotic photoreceptor cell death in three different retinal degenerations

    Proc. Natl. Acad. Sci. USA

    (1996)
  • C.K. Chen et al.

    Abnormal photoresponses and light-induced apoptosis in rods lacking rhodopsin kinase

    Proc. Natl. Acad. Sci. USA

    (1999)
  • Cited by (0)

    1

    Equally contributing authors.

    View full text