Molecular Bases of Neurodegenerative Disorders of the Retina E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Sprache: Englisch
This book focuses on the physiology and molecular biology of the front and back regions of the eye. Specifically, the chapters of this book cover topics that explain currently less understood aspects of retinal health as well as the use of zebrafish models to understand the molecular pathogenesis of associated diseases. This includes retinitis pigmentosa, diabetic retinopathy ciliopathies in the eye, rhodopsin trafficking and associated disorders, and the biochemistry of cone defects. This book serves as a useful reference for scientists and graduate students seeking to understand protein trafficking mechanisms and metabolic control in retinal diseases.
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Veröffentlichungsjahr: 2017
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Molecular Bases of Neurodegenerative
Disorders of the Retina
Edited by:
Hemant Khanna, PhD
BENTHAM SCIENCE PUBLISHERS LTD.
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PREFACE
The interpretation of light signals has fascinated as well as perplexed the minds of geniuses, including Isaac Newton, Albert Einstein and Charles Darwin. The eye is the medium through which our brain interprets the various environmental cues. It also acts as a window to the brain. Ever since humanity has developed an understanding of the ways eyes interpret light signals, many mysteries about its structure, development and function have been unearthed.
Photoreceptors (rods and cones) - which are situated in the back of the eye in a transparent tissue called Retina - form the majority of the neurons that are involved in transmitting light signals to the brain. The unique polarized morphology and physiology of the photoreceptors make them one of the most fascinating cell types. So much so, that they have been used to examine the way our eyes have evolved to interpret visual cues. In fact, photoreceptors are the first responders to light, and thus hold the bulk of our visual power. However, ‘with great power comes great responsibility’; photoreceptors have evolved stringent mechanisms to maintain their function over the lifespan of an organism. The light-sensing cellular antenna of the photoreceptors is a modified cilium. Even slight perturbations in the development, structure, or function of the cilium can result in severe blindness disorders (called ciliopathies). Innovative technological advances are rapidly leading to a better understanding of the photoreceptors, particularly with respect to the involvement of the cilia in interpreting the light signal. Moreover, defects in the retinal vasculature and neuronal degeneration are the primary cause of debilitating disorders, such as Diabetic Retinopathy and Age-related Macular Degeneration. Numerous investigations have yielded new insights on the invo-lvement of defective protein trafficking and angiogenesis in the manifestation of various eye diseases. I have compiled information from excellent investigators who have worked diligently and made seminal contributions to the field of photoreceptor development and their involvement in pathogenesis of neuronal degeneration in the retina.
My sincere thanks go to the authors for contributing chapters and highlighting their comprehensive and cutting-edge research.
List of Contributors
Ciliary Trafficking in Vertebrate Photoreceptors
Hemant Khanna*Abstract
Cilia are microtubule-based extensions of the plasma membrane of cells. These extensions detect extrinsic cues that are crucial for carrying out a myriad of developmental and homeostatic signaling cascades. Cilia have evolved diverse means to mediate signaling cascades in a cell-type specific manner. In this article, I have summarized the conserved mechanisms of formation of cilia and their structural and functional specialization for light detection.
INTRODUCTION
The cilia, Latin for ‘eyelash’, were first described by Anton van Leeuwenhoek in 1675 as ‘incredibly thin feet, or little legs, which were moved very nimbly’ [1]. Historically, although cilia were considered vestigial, notable hypotheses were put forth to understand the nature and function of cilia. For example, cilia were thought to be active organelles and that sperm flagella (or cilia) contained fibrils that extended across the entire length of the flagellum. However, these hypotheses could not be tested due to the technical limitations at the time. Cilia and flagella have now been recognized as key players in organism development and homeostasis [2].
Based on the structure and function of the microtubule skeleton, there are two types of cilia: motile cilia and primary (or immotile) cilia. As the name implies, motile cilia are involved in cell movement, such as sperm motility and mucosal clearance by the trachea. They originate from the basal body, the mother centriole in the form of microtubule extensions. The motile cilia possess 9 outer doublet microtubules and a central pair of singlet microtubules, forming a 9+2 array. Unlike motile cilia, the primary cilia display a 9+0 arrangement of microtubules due to the absence of the central microtubule pair. Both types of cilia are involved
in sensory perception, hence also termed sensory cilia. Although the motile and primary cilia are clearly distinguished based upon their motility and function, there are instances of motile cilia being sensory, such as tracheal cilia, and primary cilia show properties of motility, such as the cilia in the embryonic node [3-7].
Cilia act as a hub for G-protein coupled receptors (GPCRs) such as rhodopsin [8-10]. A conserved process called Intraflagellar Transport (IFT) regulates cilia growth and function. IFT in cilia participates in signaling pathways by concentrating cognate receptor proteins in the ciliary membrane [6] and involves movement of cargo (membrane receptors) towards cilia tip by anterograde motor Kinesin-II and back to the base driven by cytoplasmic dynein-2 motor. Previous studies have shown that IFT proteins are organized into two distinct complexes: complex A (IFT144, 140, 139, and 122) and complex B (comprising of several IFT proteins, including IFT88, 81, 80, 27, and 20) [11-14] (Fig. 1). Disruption of IFT proteins results in defective cilia formation and associated function.
Fig. (1)) Cilia: This figure depicts a simplified representation of IFT in cilia. The IFT-B particle carries cargo in anterograde direction to distal tip of cilia using the anterograde motor Kinesin-II whereas dynein and the IFT-A complex carry out retrograde movement.Given the involvement of cilia in various developmental pathways, their dysfunction is associated with severe human disorders, collectively termed ciliopathies. In fact, involvement of cilia in human diseases was first reported in a disorder of ciliary motility in patients with primary cilia dyskinesia (PCD). Although named as a dysfunction of primary cilia, which are immotile cilia, this disease is caused due to defects in motile cilia [15]. Bjorn Afzelius first identified this disorder in 1976 in patients that exhibited immotility of bronchial cilia, sperm dysfunction and ear infections [16]. PCD in association with situs inversus (reversal of the left-right asymmetry of the body) is also observed in patients with Kartagener syndrome [16-18]. In the last decade, ciliary dysfunction has been linked to numerous ciliopathies, including Meckel-Gruber syndrome, Bardet-Biedl Syndrome, Joubert Syndrome, polycystic kidney diseases, Nephrono-phthisis, Senior-Loken Syndrome, Usher Syndrome, and some forms of Retinitis Pigmentosa (RP) [3].
RP is a clinically and genetically heterogeneous group of disorders characterized by retinal degeneration due to the loss of rod and cone photoreceptors. Photoreceptor dysfunction and degeneration due to ciliary dysfunction is commonly observed in ciliopathies. In this chapter, I will briefly describe the anatomy of the eye and the retina, and focus on the involvement of cilia in the maintenance of photoreceptor structure and function. I will also briefly discuss the involvement of ciliary function in other cell types of the retina that are critical for normal vision.
EyeThe eyeball is located at a strategic position to ensure maximum light detection while securely positioned in the cavity of the orbit. It is largely divided into anterior and posterior chambers. Light enters the anterior part of the eye, which includes the cornea and the pupil, and passes through the lens to the posterior part of the eye, which is the retina; here, it activates a complex set of events. The retina then projects the signal via the optic nerve to the lateral geniculate nucleus (LGN) in the brain (Fig. 2).
There are three major fluid-filled chambers in the eye: anterior chamber, which is between the cornea and the iris; posterior chamber, between the iris and the lens and vitreous chamber, which is located between the lens and the retina and is filled with vitreous humor. The anterior and the posterior chambers are filled with a fluid called aqueous humor, which supplies nutrients to the cornea and the lens and maintains optimum pressure in the eye, called intraocular pressure (IOP). The IOP is regulated by a balanced inflow and outflow of aqueous humor from the anterior chamber into the blood stream. A major pathway for outflow of the fluid is via the trabecular meshwork tissue into Schlemm’s canal. This outflow is measured to calculate the IOP of the eye, which serves as an important risk factor for developing an incurable blindness disorder called glaucoma [19, 20].
Fig. (2))Structure of the eye. The anterior and posterior parts of the eye are represented here. The optic nerve in the back of the eye traverses to the LGN in the brain to transmit the signals to the visual cortex.Retina
The retina is the light-sensitive tissue situated in the back of the eye. It is composed of five major layers, encompassing the photoreceptor cell bodies (outer nuclear layer), the inter neurons (inner nuclear layer, consisting of both excitatory and inhibitory neurons, such as bipolar cells, amacrine cells, and horizontal cells), and the retinal ganglion cells (Fig. 3). The neural connections with dendrites and axons of the neurons are interspersed in the outer and inner plexiform layers. The light signal is processed by the photoreceptors and the change in membrane potential is relayed to the bipolar cells and then to the ganglion cells. Along the way, lateral interactions are mediated by horizontal and amacrine cells, which provide spatial cues and lateral inhibition for correct image formation.
Fig. (3))Cross section of the retina: The retina is composed of various layers of neurons as indicated. Overlaying the neurons is the retinal pigment epithelium, which supplies nourishment to the photoreceptors (rods and cones). The Ganglion cells extend the optic nerve to the brain.Photoreceptors
Photoreceptors are the most abundant cell types in the retina. There are two types of photoreceptors: rods and cones. Rods are involved in starlight or dim light vision whereas cones assist in high acuity daytime vision. The photopigment rhodopsin is expressed specifically by rods and is the most abundant protein in these neurons. The human retina contains about 120 million rods and approximately 6 million cones [21]. Depending upon the species, there are different cone subtypes, which express photopigments (opsins) that respond to specific wavelengths of light. For example, Short wave length (S; blue)-opsin expressing S-cones, Medium wave length (M; green)-opsin expressing M cones and Long wave length (L; red)-opsin expressing L cones. Primates have all three kinds of cones whereas mice only have S- and M-cones. Sequence analysis of these photopigments has revealed considerable homology and identity among the cone opsins as well as between cone opsins and rhodopsin. In fact, the L and M cone opsins share 96% identity in their amino acid sequence, indicating that they were likely derived from a gene duplication event about 30 million years ago [22-24].
Although we spend the majority of our life in well-lit environment in which only cones are functional, the human retina has a dearth of cones as compared to rods. Evolution has taken care of this skewed ratio by developing a central region in the retina, called the macula (and the central 2-3 millimeters called the fovea). This region contains only cones and no rods. Outside the macula, rods outnumber the cones. Additionally, the fovea lacks S-cones, which form ~10% of the cone population. These adaptations have led to the development of a strong and high acuity central vision due to the cones and a blurry peripheral vision mediated by the rods [25]. Rods play crucial roles in the maintenance of cone health and cone death induced retinal remodeling [26-29].
Vertebrate Photoreceptors: Modified Ciliary Neurons
Vertebrate photoreceptors are highly polarized neurons with distinct compartments for protein and lipid synthesis and for light detection. Morphologically, the photoreceptors can be divided into three major compartments: outer segment (OS), inner segment (IS), and the synaptic compartment. The bulk of protein synthesis and respiratory machinery is in the IS of the photoreceptors. All proteins and lipids necessary for the OS or the synaptic function are synthesized in the IS and then vectorially transported to their destinations. Components necessary for light detection are in the OS of the photoreceptors.
The OS is also considered a modified sensory cilium. This is because the OS shares a conserved relationship, both morphologically and physiologically, to other sensory cilia. OS formation begins when the basal body (consisting of triplet microtubules) docks at the apical region of the IS. The photoreceptor membrane forms a thin tongue-shaped microvillus extensions of the apical portion of the inner segment, which resemble the calyx of a flower. Hence, these structures are named calycal processes [30]. On the lateral walls of the ridge of the inner segment plasma membrane from which the cilium grows there are highly ordered structures forming a periciliary ridge complex (PRC). These ridges were later found to contain large molecular weight protein complexes, such as the usherin complexes [31-33].
Photoreceptors exhibit a unique property of accumulation of numerous filament, tubule and vesicle-like structures in the distal cilium. These structures successively transform into sac-like structures, called rod sacs, which then form the flattened array of membranous discs. Another intriguing early observation was the asymmetrical nature of the early stages of OS development. It was found that rod sacs, which later form the mature OS discs, develop on one side of the cilium while the other side remains largely undifferentiated [34]. Molecular mechanisms underlying such asymmetry in ciliary extension remain elusive to date. A distinguishing feature between a rod and a cone OS is that the rod discs are largely closed and are inside the ciliary membrane whereas ultrastructural analysis of the cone OS identified orderly stack of membranous lamellae that are continuous with the ciliary membrane. Some studies however, have revealed closed cone OS discs [35, 36]. Other than the morphological differences, the cytoskeletal arrangement seems similar between a rod and a cone OS.
Fig. (4))Ultrastructure of the photoreceptors. Transmission electron microscopy of adult mouse photoreceptors shows a densely-packed array of discs in the outer segment (OS) in A. Panel B depicts a transition zone (TZ) and OS of a photoreceptor. Insets show the cross sections from the TZ (doublet microtubule array) and the base of the OS (singlet microtubules). RPE: retinal pigment epithelium; IS: inner segment.Elegant studies have revealed the protein and lipid composition of the discs [37-46]. Given that photoreceptors are postmitotic neurons and are constantly processing light signal, they are under immense oxidative. It has been postulated that photoreceptors have evolved a mechanism of shedding of their distal tips and subsequent phagocytosis by the RPE (retinal pigment epithelium) to reduce the stress. To compensate for this loss of OS membranes, new discs are synthesized at the base of the OS, which requires additional protein and lipid generation and directional trafficking to the OS. Work by Richard Young, Dean Bok and colleagues revealed that the periodic shedding of the distal 10% of the OS tips in mice and phagocytosis by the RPE in conjunction with the subsequent renewal proximally confers long-term survival and maintenance of photoreceptor function. Similar processes are believed to occur in cone OS as well [47-49]. However, molecular mechanisms underlying disc formation are not completely understood. This is largely because photoreceptors are the only cell types that exhibit such a phenomenon and thus, it is hard to recapitulate such conditions in vitro. Moreover, structural constraints and tissue processing procedures make it difficult to carefully assess the mechanisms of disc formation and arrangement in intact OS.
Nonetheless, the first model to explain this complex phenomenon was proposed by Steinberg et al. (1980) [50], which was later supported with some evidence by Matsumoto and Besharse (1985) [51]. This model, termed ‘evagination model’ proposed that new discs are formed by evagination of the basal OS plasma membrane based on the observation of open discs during ultrastructural analyses. After about 22 years, Ching-Hwa Sung and colleagues proposed an alternative model called ‘vesicular targeting model’, according to which rhodopsin-containing vesicles associated with Smad Anchor for receptor Activation (SARA), syntaxin 3 and phosphatidylinositol 3-phosphate (PI3P) are incorporated into discs during disc formation. This model posits an absence of open nascent discs and that disc formation and rhodopsin incorporation occur simultaneously inside the OS [52, 53]. Although vesicles at the base of the OS were not observed in a subsequent cryo-electron tomography analysis of 3D maps of mammalian photoreceptor cilium, absence of ‘open discs’ was confirmed in that analysis [54]. A series of recent publications have further examined the mode of disc morphogenesis in vertebrate species. These studies provide compelling evidence for the evagination model for disc morphogenesis in rod photoreceptors [55-57].
Phototransduction: A Ciliary Phenomenon
The opsin molecule, a G protein coupled receptor, is inserted in the disc membrane and dos not respond to light until bound to the light-sensitive chromophore 11-cis retinal. Photon capture by the chromophore causes it to isomerize to all-trans retinal, resulting in a conformational change in the opsin (Metarhodopsin II). This step is the only light-dependent step in the cascade. Metarhodopsin II dissociates from the retinal and diffuses in the disc membrane where it interacts with the GDP-bound small GTPase transducin. This interaction activates transducin to bind to GTP, which subsequently dissociate into GTP-bound α-subunit (Tα−GTP) and a βγ subunit (Tβγ). Tα−GTP associates with cyclic nucleotide phosphodiesterase, which leads to the hydrolysis of cGMP. In the dark, the concentration of cGMP, which serves as a messenger to the plasma membrane, is high, which results in an influx of Na+ and Ca2+ ions through the depolarized open cyclic nucleotide gated channel. However, the decrease in the cGMP concentration due to its hydrolysis in light results in the closure of the CNG channel, consequent decrease in the Na+ and Ca2+ concentration and hyperpolarization of the cell. This leads to the decrease in the release of the neurotransmitter, thereby initiating the neural signal. Additional mechanisms are also in place to terminate the cascade. The signal is transmitted by synaptic activity to the inner neurons: bipolar cells, amacrine cells, horizontal cells and in the end to output neurons called retinal ganglion cells. The axons of the ganglion cells transmit the information to the brain by forming the optic nerve [20, 21, 58, 59].
In addition to the phototransduction cascade, the photoreceptor cilia also communicate with the RPE to regenerate the chromophore. The all-trans retinol dissociated from Metarhodopsin-II is transported to the RPE, where it goes through a series of well-described reactions, mediated by enzymes such as RPE65 and LRAT to 11-cis retinol and subsequently to 11-cis retinal, which is subsequently transported back to the OS. This portion of the signaling cascade is called visual cycle [19].
Cilia in Other Cell Types Involved in Vision
As detailed above, massive amount of work has been done to understand the role of cilia in photoreceptor biology. This is largely because of the overwhelming majority of photoreceptors in the retina. In a recent study, presence of primary cilia in other mouse retinal cell types was investigated using specific antibodies against marker proteins. Ciliary staining was observed, in addition to photoreceptors, in the synaptic layer and ganglion cell layer [60]. These invest-igations also suggest that the synapses may share features of cilia and the inner retinal cell types may not necessarily develop cilia as organelles. Interestingly, primary cilia were detected in rat Muller glia and defects in ciliary function was shown to affect the proliferation and dedifferentiation of these cell types in culture [61]. Additional investigations are necessary to unravel the presence and function of cilia in other retinal cell types.
Retinal Pigment Epithelium (RPE)
RPE cells in culture are shown to form primary cilia. In fact, cultured RPE cells are used as a model to examine cilia biogenesis and function [62]. However, the in vivo role of cilia in the RPE is not completely understood. In fact, the localization of cilia in the RPE is technically challenging due to the formation of apical processes in the apical RPE. If cilia are also present, they might be involved in sensing the signals from the OS tips during phagocytosis. One study showed that rat RPE develops cilia transiently during rat development and this ciliogenesis is associated with expression levels of the Claudin protein [63]. Hence, it is possible that cilia perform a developmental role in RPE-retina interaction.
Endothelial Cells
The retina is separated from blood vessels by the blood-retinal barrier. This is divided into two parts: inner barrier, which is composed of the retinal capillary endothelial cells, Muller glia and the pericytes and nourishes the inner retina, and outer barrier, which is formed by the RPE cells between outer retina and the choroidal endothelial blood vessels [64]. Disruption of the blood retinal barrier is associated with devastating blindness diseases, diabetic retinopathy and neo-vascular AMD (age-related macular degeneration). In DR, the damage to the blood vessels of the retina occurs due to diabetic complications. On the other hand, AMD is a slow and progressive loss of vision that usually starts in old age (~60 years or older). The vision problems happen due to the loss of the photoreceptors in the macular (central) region of the retina. One mechanism of DR and AMD progression is angiogenesis, which is the expansion of existing blood vessels, from retinal or choroidal endothelial cells. It has been shown that endothelial cells form primary cilia, which act as shear stress sensors in response to blood flow [65]. It would be interesting to assess any possible relationship between endothelial cilia and the pathogenesis of DR and AMD has not been examined.
Anterior Segment
A recent study from Young Sun and colleagues demonstrated the involvement of cilia and ciliary signaling in the maintenance of intraocular pressure (IOP), aberrations in which are associated with the pathogenesis of glaucoma [66
