Ординатура / Офтальмология / Английские материалы / Essentials in Ophthalmology Pediatric Ophthalmology Neuro-Ophthalmology Genetics_Lorenz, Borruat_2008

The nature of the visual field defect, description of photopsias and, in some cases, night-blindness or decreased vision in bright light, history of cancer, subtle fundus changes, ERG and fluorescein angiography can help to differentiate these patients from those with primarily neuroophthalmic problems, and lead to the correct diagnosis.

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11.1Introduction

A common hallmark of retinal diseases is the selective loss of retinal neurons, mostly photoreceptor cells or retinal ganglion cells (RGC). Retinal degenerative diseases are classified in three major groups: those affecting primarily photoreceptors [retinitis pigmentosa (RP) and related diseases], those involving the retinal pigment epithelium (RPE) but affecting photoreceptors [e.g. age-related macular degeneration (AMD)], and those affecting RGC (glaucoma).

11.1.1 Retinitis Pigmentosa

Most diseases of the RP group are caused by single gene mutations, which contribute to photoreceptor death. Over 100 single gene mutations for RP have been identified, most of them causing decline of rods selectively, while cones often undergo apoptotic cell death secondarily to rods and are seldom directly affected by the mutations. As a consequence, a first symptom in diseases of the RP group is often night-blindness due to destruction of rods, followed by loss of central vision and complete blindness due to dying cones. Approximately 1 in 3000 individuals worldwide

186Retinal Research: Application to Clinical Practice

suffers from RP, which is the leading cause of inherited blindness in the developed world. There is no efficient treatment for this large group of retinal degenerative diseases. Future strategies developed from data collected in animal models comprise the application of neuroprotective factors, transplantation of stem cells, RPE or retinal sheets, gene therapy and others.

11.1.2Age-Related Macular Degeneration

The AMD group mostly consists of diseases caused by polygenic incidents with a strong environmental influence. It shows a high prevalence in industrialized countries and is expected to increase significantly in the coming decades: between 10% and 20% of people over the age of 65 years suffer from maculopathy, an early stage of AMD or of overt macular degeneration, mak-

11 ing AMD the most common cause of blindness in older patients in developed countries. By 2020, the number of AMD patients is expected to increase by 50%. In AMD central visual acuity is lost due to degeneration of photoreceptor cells in the macula. Loss of cone and rod cells in AMD is a secondary effect following the degeneration of the adjacent RPE, which – in its healthy state

– is responsible for removal of photoreceptor cell debris generated during the phototransduction cascade. Early AMD is recognized by the presence of yellow deposits beneath the retina called drusen and pigmentary changes following atrophy and/or proliferation/de-differentiation of the RPE. At later stages, often two clinical subtypes can be identified. The most common one is “wet” or exudative AMD. It is associated with abnormal vessels that proliferate from the choroid into the subretinal space and retina resulting in fluid and blood leakage, with secondary damage to the photoreceptive structures. Detachment of the RPE and fibrosis are common symptoms in late AMD. The second clinical subtype is a “dry” retinal atrophy, which often involves spots of the retina responsible for central visual acuity, such as the fovea. Current treatment strategies use thermal laser photocoagulation to stop neovascular growth in the choroid at advanced stages of wet AMD, although this simultaneously destroys

the overlying retina. A more gentle approach combines intravenous infusion of the light-sen- sitive dye verteporfin, which is activated inside the neovascularized area by a low-intensity laser in order to occlude pathologic vessels without touching the overlying retina.

11.1.3 Glaucoma

Glaucoma is caused by high intraocular pressure, resulting for example from oxidative stress, deficiency of neurotrophic factors, and various other pathogenic origins, leading to RGC death and optic nerve degeneration. Glaucoma accounts for around 11% of diseases accompanied by low vision. Presently, glaucoma therapy aims at reducing the intraocular pressure, hence protecting the optic nerve function. However, when intraocular pressure is lowered by medication or surgery, progression of disease does not slow down in all patients. Moreover, a substantial number of patients (about one-third) show a form of glaucoma without elevated intraocular tension making it necessary to look for neuroprotective treatments in glaucoma besides pressure-lowering surgery.

In all of these diseases the visual system can be severely and irreversibly damaged, resulting in ongoing loss of visual function and often ending in complete blindness. The major goal of all different treatments is to preserve, protect, and rescue the declining cells, and ultimately to prevent blindness. However, proven strategies for prevention and treatment are not numerous. Previous and current research targeting cell loss aims to: (1) protect dying cells from cell death,

(2) replace degenerated cells by transplantation, or (3) replace degenerated cells by endogenous cellular sources. This chapter will review current research in this field, summarizing possible future therapeutic approaches.

11.2 Cell Death in the Retina

It is well established that apoptosis is the final cell death pathway in RP, AMD and glaucoma. Tissues undergoing programmed cell death in these diseases are photoreceptor layers in the case of RP and the RPE in the case of AMD, whereas in

glaucoma the decline of RGCs provokes similar symptoms such as loss of visual function. However, knowledge about pro-apoptotic cues during retinal dystrophy and degeneration is scarce. Although a great number of gene mutations triggering RP and AMD have been identified, many questions remain as to which molecular mechanisms are accompanied by apoptotic events in this context. Investigating causative signals and resulting mechanisms of apoptosis in these blinding diseases is a major task: better discernment of related events might provide a powerful handle to develop rescue strategies against progressive cell loss in the visual system. This review starts with a summary of what is known on cell death pathways in general, followed by an overview of possible survival-promoting and cell-replace- ment strategies, including the stimulation of endogenous regeneration.

11.2.1Major Characteristics

and Pathways of Apoptosis

The development and maintenance of an organism demand not only cell proliferation, but also the removal of surplus or damaged cells that otherwise might affect the correct functioning of organs or even endanger the survival of the entire system. Controlled execution of cell death, classically referred to as apoptosis, is usually finely tuned during development and in the adult. Histogenesis and tissue homeostasis in mature individuals depend largely on the regulated elimination of individual cells. However, exogenous stimuli or endogenous gene mutations may affect this highly regulated process and lead to neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease in the brain, or RP and AMD in the retina [20].

Apoptotic cells were first identified on the basis of their morphology, characterized by condensation of chromatin, membrane blebbing and disintegration of dying cells into apoptotic bodies, which are then removed by phagocytic cells. In addition, details on physiological changes that correlate with alterations in cell architecture have been observed, such as inter-nucleosomal DNA cleavage and exposure of phosphatidylserine to the outside of cellular membranes. Specific en-

11.2  Cell Death in the Retina 187

dopeptidases called caspases have been identified as central tools that drive programmed cell death to its endpoint. The classical concept of apoptosis being initiated and executed by caspases has recently been complemented by cas- pase-independent mechanisms of apoptosis. While the first work through aspartate-specific endopeptidases, the latter can depend on a variety of factors, including proteases, apoptosisinducing factor (AIF), endonuclease G (EndoG), proteasomes and lysosomes. An increasing number of caspase-independent mechanisms are still being explored. While discovering new pathways of apoptosis besides the caspase-depen- dent mechanisms it became clear that apoptosis might involve various cellular compartments in addition to mitochondria, such as lysosomes, the endoplasmic reticulum, the Golgi apparatus, proteasomes or autophagic vacuoles. The different mechanisms of programmed cell death and apoptosis are summarized in Table 11.1.

11.2.1.1Caspase-Dependent Apoptosis

Caspases are endopeptidases that cleave distinct polypeptides – over 100 different substrates are known – on the carboxyl side of aspartate residues. To enter a caspase-dependent pathway of apoptosis, caspases need to be activated by other enzymes. Caspases are synthesized as zymogens and consist, in their inactivated form, of an N-terminal prodomain, and a large and a small subunit. Upon cleavage by a cas- pase-dependent process, large and small subunits are released and form the activated caspase comprising two large and two small subunits. Classification of caspases describes two major groups. The first group seems to participate in cytokine cleavage and maturation (caspases-1, -4, -5, -11, -12, and -14), whereas the second group (caspases-2, -3, -6, -7, -8, -9, and -10) acts on apoptosis by cleaving various intracellular proteins. In a mechanistic approach, caspases associated with apoptosis have been divided into upstream or initiator caspases (e.g., caspases-8, -9, and -10) and their downstream targets known as effector or executioner caspases (e.g., caspases- 3, -6, and -7).

11

extensively that differ in their way of initiation, but converge at some point to one common path: the death receptor-mediated or extrinsic pathway and the mitochondrial-mediated or intrinsic pathway. The extrinsic type starts from binding of extracellular ligands to specific receptors (e.g., Fas/CD95 or tumor necrosis factor alpha, TNFα). Death domains of these receptors subsequently cluster in the plasma membrane and recruit adaptor molecules such as FADD or RAIDD. The latter activate procaspase-8 leading either directly to the activation of effector caspases such as cas- pase-3 or to the cleavage of Bid, a member of the Bcl-2 family of proteins residing in the outer mitochondrial membrane. Bid cleavage facilitates the release of cytochrome c from mitochondria, thereby converging with the second pathway of caspase activation described below.

The intrinsic pathway to caspase activation directly induces the release of cytochrome c from the mitochondrial intermembrane space. Therefore, it relies on mitochondrial membrane permeabilization without involving death receptors. Besides Bid and other members of the Bcl-2 family of proteins, it can be regulated by proteases as well as by agents that increase the permeability of mitochondrial membranes directly (reviewed in [27]). After its release to the cytosol,

tosome. Downstream follows the activation of effector caspases-3 and -7 eliciting ultrastructural features characteristic of the apoptotic process, which is synonymous with entering the degradation phase.

11.2.1.2Caspase-Independent Apoptosis

An overall property of apoptosis is the proteolytic degradation of proteins, but the caspases are not the only executioners of the apoptotic program. It has been shown that inhibition of caspases cannot block apoptosis in cultured cells that had been exposed to toxic stimuli. Moreover, apoptosis reportedly occurs in the absence of caspases in many in vivo cell death models (reviewed by [27]). Non-caspase proteases that have been implicated in apoptotic cell death are cathepsins, calpains, granzymes, serine proteases and proteasomal proteases.

From the cathepsin family, cathepsin B and L (both cysteine proteases) as well as cathepsin D (an aspartate protease) have been proven to play a role in apoptosis through their translocation from lysosomes or endosomes to the cytosol. Calpain proteases, a family of cysteine proteases

residing in the cytosol, are activated by increased intracellular Ca2+ concentrations. In particular, m-calpain and µ-calpain seem to be linked to apoptotic processes, as has been shown to occur in Alzheimer and Parkinson’s disease. Granzymes specifically cleave proteins on the carboxy side of acidic amino acid residues, most often aspartate. Secretion of granzymes to the extracellular space attracts natural killer cells that consequently induce apoptosis. Omi/HtrA2 is a serine protease sitting in the mitochondrial intermembrane space that is released to the cytosol upon various apoptotic stimuli and can induce apoptosis via its protease activity. Proteasomal proteases can influence the stability of apoptotic regulators from the Bcl-2 and IAP families thereby acting on apoptosis.

In addition to proteolysis, more caspase-inde- pendent mechanisms have been reported: death effectors such as AIF can be released from the mitochondrial intermembrane space following permeabilization of this membrane in a caspaseindependent manner. AIF translocates to the nucleus where it starts chromatin condensation and DNA fragmentation by recruiting or activating an endonuclease. EndoG, the most abundant endonuclease in mitochondria of eukaryotic cells, follows a similar pathway as AIF and can promote nuclear degradation in apoptosis.

In addition to these death effectors, an imbalance in reactive oxygen species (ROS) production can be a powerful pro-apoptotic stimulus. Again, mitochondria are the focus of attention: overproduction of ROS in mitochondria can

–via its influence on membrane permeability

–provoke osmotic swelling of these organelles and physical rupture, releasing a vast amount of pro-apoptotic factors into the cytosol. Similar effects have been reported for reactive nitrogen species (RNS). Increased levels of intracellular Ca2+, caused for example by instability of the endoplasmic reticulum, and excess calcium can activate Ca2+-dependent enzymes such as calpains and endonucleases.

This summary of what is known on apoptosis in general has made clear that there is no real limitation in apoptotic mechanisms but rather a manifold amount of pro-apoptotic stimuli exists. Recent evidence has shown that caspases can no longer be termed sole central effectors of apoptosis. The ever-increasing non-caspase effectors

may represent failsafe mechanisms for apoptotic cell elimination [27]. The great number of possible mechanisms was described almost exclusively in non-ocular tissues and might be true for the retina as well, although there are few data on which apoptotic mechanisms exactly contribute to neurodegenerative diseases in the eye [59].

Summary for the Clinician

■The existence of very different apoptotic mechanisms presents a current limitation in the identification of anti-apop- totic drug targets and drugs.

11.3Therapeutic Strategies in Degenerative Retinal Diseases

11.3.1Strategies

for Neuroprotection

11.3.1.1Animal Models in Retinal Degeneration Research

A promising way of preventing programmed cell death is the application of neuroprotective factors such as cytokines, antioxidants or calcium antagonists. A broad set of substances has been examined with respect to their influence on cell death in all kinds of animal models. While for antioxidants and calcium antagonists the mechanism of cell rescue is quite obvious, for most of the cytokines molecular interactions remain to be elucidated. Studies on apoptosis are performed in animal models that use light-induced retinal degeneration or in animal models for inherited RP. Both models share the mechanism of cell death by apoptosis with corresponding inherited human diseases.

Substances that protect neurons from dying in both light damage and animal models of inherited forms of RP are particularly promising. Several aspects need to be taken into account when comparing these two different experimental setups. The number of mice models mimicking human inherited degenerations is constantly growing. Genetically engineered mouse models

190Retinal Research: Application to Clinical Practice

carrying a mutation described in patients are powerful tools with which to connect the failure of specific genes with their molecular outcome in diseased retinal cells. In order to work out preventive strategies for human degenerative diseases, exploring specific cell death mechanisms in this context is especially valuable. However, studying apoptosis in these inherited models needs to overcome several obstacles, as the time course of programmed cell death differs widely between individual models, and the onset of apoptosis is different in individual retinal cells of the same model. It can take a substantial amount of a mouse’s lifetime for symptoms to emerge, and at a given time point only a small number of cells will be at the same stage of decline. For comparison, light damage animal models, where excessive light induces apoptosis in photoreceptor cells, show fast and reproducible retinal de-

generation. In these models apoptosis proceeds through its characteristic steps simultaneously in 11 all affected photoreceptors, which is a prerequisite for identifying molecular markers that correlate with distinct steps of programmed cell death. Light-induced and inherited models also differ in another respect: whereas the first sometimes show complete retinal regeneration following a specific treatment, in the latter persistent genetic mutations at best slow degeneration down [59]. However, compounds that are protective in both light-induced damage models and inherited degeneration have proven to be beneficial in several

aspects and therefore seem to be promising candidates for preventing photoreceptor cell death.

While many mouse models for RP exist, only a few are suitable for AMD. An exception to this rule are two models showing several morphological features of AMD including drusen, apoptotic cell death and neovascularization: Ccl2(–/–) or Ccr2(–/–) mice show impaired macrophage recruitment which may contribute to AMD pathogenesis. Another model mimicking symptoms of macular degeneration is the abcr–/– knockout mouse model for Stargardt’s disease. This inherited disease is characterized by macular degeneration and accumulation of toxic lipofuscin deposits in the retina similar to pathologic events in AMD. In all of these mouse models for AMD the conversion from non-neovascular to neovascular tissue seems to be accompanied by increased expression of vascular endothelial growth factor (VEGF), probably inducing choroidal vessels to infiltrate retinal structures [40].

11.3.1.2Strategies

for Neuroprotection Interfering

with the Induction Phase of Apoptosis

Different neuroprotective strategies are summarized in Table 11.2. Correct function of the visual cycle has been shown to be a prerequisite