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Programmed Non-Apoptotic Cell Death in Hereditary Retinal Degeneration: Crosstalk between cGMP-Dependent Pathways and
1Cell Death Mechanism Group, Institute for Ophthalmic Research, University of Tübingen, Elfriede-Aulhorn-Strasse 7, 72076 Tübingen, Germany.
Abstract:
Programmed cell death (PCD) is a highly regulated process that results in the orderly destruction of a cell. Many different forms of PCD may be distinguished, including apoptosis, PARthanatos, and cGMP-dependent cell death. Misregulation of PCD mechanisms may be the underlying cause of neurodegenerative diseases of the retina, including hereditary retinal degeneration (RD). RD relates to a group of diseases that affect photoreceptors and that are triggered by gene mutations that are often well known nowadays. Nevertheless, the cellular mechanisms of PCD triggered by disease-causing mutations are still poorly understood, and RD is mostly still untreatable. While investigations into the neurodegenerative mechanisms of RD have focused on apoptosis in the past two decades, recent evidence suggests a predominance of non-apoptotic processes as causative mechanisms. Research into these mechanisms carries the hope that the knowledge created can eventually be used to design targeted treatments to prevent photoreceptor loss. Hence, in this review, we summarize studies on PCD in RD, including on apoptosis, PARthanatos, and cGMP-dependent cell death. Then, we focus on a possible interplay between these mechanisms, covering cGMP-signaling targets, overactivation of poly(ADP-ribose)polymerase (PARP), energy depletion, Ca2+-permeable channels, and Ca2+-dependent proteases. Finally, an outlook is given into how specific features of cGMP-signaling and PARthanatos may be targeted by therapeutic interventions.
Insights
Programmed cell death (PCD) mechanisms, including apoptosis and PARthanatos, are implicated in retinal degeneration (RD). Understanding these pathways offers hope for new treatments to prevent photoreceptor loss.
Area of Science:
- Cell Biology
- Neuroscience
- Ophthalmology
Background:
- Programmed cell death (PCD) is crucial for cellular homeostasis, with dysregulation linked to neurodegenerative diseases like hereditary retinal degeneration (RD).
- While apoptosis was historically the focus, recent research highlights non-apoptotic PCD pathways in RD pathogenesis.
- RD affects photoreceptors due to gene mutations, leading to vision loss, yet effective treatments remain elusive due to poorly understood cellular mechanisms.
Purpose of the Study:
- To review current knowledge on PCD mechanisms, including apoptosis, PARthanatos, and cGMP-dependent cell death, in the context of RD.
- To explore the interplay between these PCD pathways and their molecular underpinnings in photoreceptor degeneration.
- To identify potential therapeutic targets within cGMP-signaling and PARthanatos for treating RD.
Main Methods:
- Literature review of studies on PCD in hereditary retinal degeneration.
- Analysis of research focusing on apoptosis, PARthanatos, and cGMP-dependent cell death in RD.
- Examination of molecular mechanisms involving cGMP signaling, PARP overactivation, energy depletion, and calcium-mediated pathways.
Main Results:
- Evidence suggests non-apoptotic PCD pathways, such as PARthanatos and cGMP-dependent cell death, play a significant role in RD.
- An intricate interplay exists between cGMP signaling, poly(ADP-ribose)polymerase (PARP) overactivation, energy depletion, and calcium homeostasis in driving photoreceptor cell death.
- Specific molecular targets within these pathways have been identified as potential points for therapeutic intervention.
Conclusions:
- Non-apoptotic PCD mechanisms are critical contributors to photoreceptor loss in hereditary retinal degeneration.
- Targeting specific components of cGMP signaling and PARthanatos presents a promising therapeutic strategy for RD.
- Further research into the complex interplay of these cell death pathways is essential for developing effective treatments for untreatable retinal degenerations.
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