Novel Programmed Cell Death as Therapeutic Targets in Age-Related Macular Degeneration?

Abstract

Age-related macular degeneration (AMD) is a leading cause of severe visual loss among the elderly. AMD patients are tormented by progressive central blurring/loss of vision and have limited therapeutic options to date. Drusen accumulation causing retinal pigment epithelial (RPE) cell damage is the hallmark of AMD pathogenesis, in which oxidative stress and inflammation are the well-known molecular mechanisms. However, the underlying mechanisms of how RPE responds when exposed to drusen are still poorly understood. Programmed cell death (PCD) plays an important role in cellular responses to stress and the regulation of homeostasis and diseases. Apart from the classical apoptosis, recent studies also discovered novel PCD pathways such as pyroptosis, necroptosis, and ferroptosis, which may contribute to RPE cell death in AMD. This evidence may yield new treatment targets for AMD. In this review, we summarized and analyzed recent advances on the association between novel PCD and AMD, proposing PCD’s role as a therapeutic new target for future AMD treatment.

Protective Effects of Fermented Paprika (Capsicum annuum L.) on Sodium Iodate-Induced Retinal Damage

“…The cell death process of apoptosis is responsible for the cell loss seen in several disorders of retina, glaucoma, and macular degeneration [ 27 , 28 ]. Evidence indicates that caspases play a key role in both the initiation and execution pathways of apoptosis [ 29 , 30 ]. Similarly, the cleavage of PARP-1 by caspases is also considered to be a hallmark of apoptosis [ 31 ].…”

Differential Retinal Protein Expression in Primary and Secondary Retinal Ganglion Cell Degeneration Identified by Integrated SWATH and Target-Based Proteomics

“…Ferroptosis is an iron-dependent non-apoptotic programmed necrosis, which is initiated by iron accumulation and overload, causing lipid ROS and cellular membrane damage. This novel programmed cell death has been recently implicated in retinal degeneration [44,45]. Secondly, there was a cluster of protein-protein interactions of regulated proteins, including serotransferrin (TF), ceruloplasmin (CP), alpha-1-macroglobulin (A1M/PZP), alpha-2macroglobulin (P06238), transthyretin (TTR), high-molecular-weight kininogen (KNG1), and apolipoprotein E (APOE), suggesting the possible imbalance of ROS due to vascular and inflammatory alteration in the retina [46].…”

Oxidative and Nitrosative Stress in Age-Related Macular Degeneration: A Review of Their Role in Different Stages of Disease

“…In ARPE-19 cells, the accumulation of excessive amounts of ROS triggers the activation of the nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, an important regulator of the secretion of different pro-inflammatory cytokines, through the increase in lysosomal membrane permeabilization, the activation of the mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways, and probably also local activated microglial cells [ 90 , 91 , 92 ]. The mechanisms leading to RPE cell death induced by oxidative stress are still poorly understood [ 93 ] and, even if apoptosis has been the most studied mechanism of programmed cell death (PCD) in the RPE [ 94 ], more recent studies have suggested that other forms of PCD, such as necroptosis (a form of regulated necrosis) and ferroptosis (a form of iron-dependent non-apoptotic programmed necrosis), could be involved in AMD pathogenesis [ 93 , 95 , 96 , 97 , 98 , 99 ].…”