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Mechanisms of Photoreceptor Death in Retinitis Pigmentosa

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Mechanisms of Photoreceptor Death in Retinitis Pigmentosa G C A T T A C G G C A T genes Review Mechanisms of Photoreceptor Death in Retinitis Pigmentosa Fay Newton 1,* and Roly Megaw 1,2 1 MRC Human Genetics Unit, University of Edinburgh, South Bridge, Edinburgh EH8 9YL, UK; [email protected] 2 Princess Alexandra Eye Pavilion, NHS Lothian, Edinburgh EH3 9HA, UK * Correspondence: [email protected] Received: 2 September 2020; Accepted: 22 September 2020; Published: 24 September 2020 Abstract: Retinitis pigmentosa (RP) is the most common cause of inherited blindness and is characterised by the progressive loss of retinal photoreceptors. However, RP is a highly heterogeneous disease and, while much progress has been made in developing gene replacement and gene editing treatments for RP, it is also necessary to develop treatments that are applicable to all causative mutations. Further understanding of the mechanisms leading to photoreceptor death is essential for the development of these treatments. Recent work has therefore focused on the role of apoptotic and non-apoptotic cell death pathways in RP and the various mechanisms that trigger these pathways in degenerating photoreceptors. In particular, several recent studies have begun to elucidate the role of microglia and innate immune response in the progression of RP. Here, we discuss some of the recent progress in understanding mechanisms of rod and cone photoreceptor death in RP and summarise recent clinical trials targeting these pathways. Keywords: retinitis pigmentosa; photoreceptor; inherited retinal disease; apoptosis; regulated necrosis; autophagy; microglia; clinical trials 1. Introduction Retinitis pigmentosa (RP) is an inherited retinal dystrophy affecting 1 in 3000 people globally [1]. Mutations in one of over 150 causal genes identified to date leads to the classical clinical appearance of bone spicule formation in the peripheral retina, blood vessel attenuation and optic disc pallor. The disease is characterised by the progressive degeneration and death of rod photoreceptors, resulting in an initial loss of night vision (nyctalopia) and a progressive constriction of the visual field. Once rod cells are severely depleted, non-autonomous death of cones results, causing severe central visual loss [1,2]. RP can be inherited in an autosomal dominant, autosomal recessive, X-linked or mitochondrial manner and can be either syndromic or non-syndromic [2,3]. Genes have been identified that are involved in phototransduction, cell trafficking and rhodopsin recycling pathways [3–5]. However, despite knowledge of how these mutations disrupt photoreceptor function, the precise mechanisms that lead to photoreceptor death are still not well understood. Given the extremely heterogeneous nature of RP, identifying and understanding common cell death mechanisms is vital if we are to develop treatments applicable to all disease-causing alleles. This review brings together some of the recent work to identify cell death pathways involved in RP and the mechanisms that link causative mutations to initiation of these pathways. Genes 2020, 11, 1120; doi:10.3390/genes11101120 www.mdpi.com/journal/genes Genes 2020, 11, 1120 2 of 29 2. Cell Death Mechanisms 2.1. Apoptosis Apoptosis is the most well studied form of programmed cell death and has long been considered to be the predominant mechanism in neurodegenerative diseases, including retinal degeneration [6–8]. Crucially, apoptosis is characterised by the sequestering of cellular components and removal of cell debris, thus minimising damage to the surrounding tissue. Initiation of apoptosis depends on the activation of caspase proteins. Intrinsic activation of apoptosis through detection of cell damage or loss of survival signals leads to increased expression of pro-apoptotic proteins such as Bax, resulting in the release of mitochondrial proteins, including cytochrome c [9]. Cytoplasmic cytochrome c forms a complex with Apoptotic Protease Activating Factor 1 (APAF1) and caspase-9, termed the apoptosome. Activated caspase-9 in this complex then cleaves and activates executioner caspasesGenes 2020(caspase-3,, 11, x FOR PEER 6 and REVIEW 7) [9, 10]. This results in a cascade of events ending in DNA and2 of protein29 fragmentation,2.1. Apoptosis chromatin and cytoskeleton condensation and the formation of apoptotic bodies (see Figure1B). Apoptosis can also be activated extrinsically following interaction between ligands producedApoptosis by immune is the cells most and well death studied receptors form of (suchprogrammed as Tumour cell death Necrosis and has Factor long (TNF)been considered or Fas) on the to be the predominant mechanism in neurodegenerative diseases, including retinal degeneration [6– surface of damaged cells. Ligand-bound receptors recruit and activate caspase-8 and this ultimately 8]. Crucially, apoptosis is characterised by the sequestering of cellular components and removal of leadscell to debris, activation thus ofminimising executioner damage caspases to the andsurroundi apoptoticng tissue. body Initiation formation of apoptosis [10]. depends on the activation of caspase proteins. Intrinsic activation of apoptosis through detection of cell damage or 2.2. Regulated Necrosis loss of survival signals leads to increased expression of pro-apoptotic proteins such as Bax, resulting inAlthough the release photoreceptorof mitochondrial proteins, death by including apoptosis cytochrome has beenc [9]. Cytoplasmic reported cytochrome in models c forms of retinal degenerationa complex[7 ,with8,11 ,12Apoptotic], there isProtease growing Activating evidence Factor that caspase-independent 1 (APAF1) and caspase-9, cell death termed mechanisms the are alsoapoptosome. involved Activated in many blindingcaspase-9 diseases, in this complex including then RP. cleaves Indeed, and some activates recent executioner studies have caspases suggested (caspase-3, 6 and 7) [9,10]. This results in a cascade of events ending in DNA and protein that these alternative mechanisms may be the dominant modes of cell death in RP [13,14]. Several forms fragmentation, chromatin and cytoskeleton condensation and the formation of apoptotic bodies (see of regulatedFigure 1B). necrosis Apoptosis have can recently also be been activated described; extrinsically including following necroptosis, interaction ferroptosis, between pyroptosis ligands and parthanatosproduced [15 by,16 immune]. The common cells and outcomedeath receptors of all these (such mechanisms as Tumour Necr is theosis breakdown Factor (TNF) of theor Fas) cytoplasmic on membrane,the surface and theof damaged resulting cells. tissue Ligand-bound damage elicits receptors a strong recruit inflammatory and activate response. caspase-8 However, and this diff erent molecularultimately pathways leads to are activation involved of executioner in their initiation. caspases and apoptotic body formation [10]. Figure 1. Cont. Genes 2020, 11, 1120 3 of 29 Genes 2020, 11, x FOR PEER REVIEW 3 of 29 FigureFigure 1. Cell 1. Cell death death mechanisms mechanisms in in Retinitis Retinitis pigmentosa (RP). (RP). (A ()A Schematic) Schematic of a ofrod a photoreceptor. rod photoreceptor. (B) Both(B) Both intrinsic intrinsic pathways pathways (through (through detectiondetection of of cell cell damage) damage) and and extrinsic extrinsic pathways pathways (through (through interactioninteraction with with immune immune cells cells and and death death receptors)receptors) ca cann lead lead to to apoptosis. apoptosis. Both Both pathways pathways lead leadto the to the releaserelease of CytC of CytC from from mitochondria mitochondr andia and oligomerisation oligomerisation of of CytC, CytC, APAF1APAF1 and pro-caspase-9 to to form form the apoptosome.the apoptosome. Activated Activated caspase-9 caspase-9 cleaves clea executionerves executioner caspases caspases 3 and3 and 7. 7. ( C(C)) PhotoreceptorPhotoreceptor death death can occurcan by occur various by formsvarious of forms regulated of regulated necrosis. necrosis. Necroptosis Necroptosis requires requires activation activation of RIP1 of RIP1/RIP3,/RIP3, leading to theleading activation to the and activation oligomerisation and oligomerisation of MLKL, of which MLKL, forms which pores forms in po theres cytoplasmic in the cytoplasmic membrane. membrane. Parthanatos can occur following activation of PARP, which can be induced by high cGMP Parthanatos can occur following activation of PARP, which can be induced by high cGMP levels, levels, leading to nuclear translocation of AIF. Some RP-causing mutations may lead to elevated Fe2+ leading to nuclear translocation of AIF. Some RP-causing mutations may lead to elevated Fe2+ and/or and/or inhibition of GPX4, causing increased lipid oxidation and death by ferroptosis, although the inhibitionmechanism of GPX4, is not causing known. increased (D) Macroautophagy lipid oxidation can be and initiated death by by endoplasmic ferroptosis, althoughreticulum (ER) the mechanism stress is notvia known. ATG12 ( Dactivation,) Macroautophagy direct activation can be of initiated ATG18/WIP12 by endoplasmic and activation reticulum of beclin1. (ER) Phagophores stress via ATG12 activation,engulf large direct cellular activation components of ATG18 and/ WIP12fuse with and lysosomes activation to form of beclin1. autophagosomes Phagophores and lysosomal engulf large cellularenzymes components then degrade and the fuse contents with lysosomes of autophagosomes. to form autophagosomesProteins also enter andlysosomes lysosomal by hsc-70- enzymes thenassisted degrade chaperone-mediated the contents
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