Cellular mechanisms of hereditary photoreceptor degeneration – Focus on cGMP

Research output: Contribution to journalReview article

Abstract

The cellular mechanisms underlying hereditary photoreceptor degeneration are still poorly understood, a problem that is exacerbated by the enormous genetic heterogeneity of this disease group. However, the last decade has yielded a wealth of new knowledge on degenerative pathways and their diversity. Notably, a central role of cGMP-signalling has surfaced for photoreceptor cell death triggered by a subset of disease-causing mutations. In this review, we examine key aspects relevant for photoreceptor degeneration of hereditary origin. The topics covered include energy metabolism, epigenetics, protein quality control, as well as cGMP- and Ca2+-signalling, and how the related molecular and metabolic processes may trigger photoreceptor demise. We compare and integrate evidence on different cell death mechanisms that have been associated with photoreceptor degeneration, including apoptosis, necrosis, necroptosis, and PARthanatos. A special focus is then put on the mechanisms of cGMP-dependent cell death and how exceedingly high photoreceptor cGMP levels may cause activation of Ca2+-dependent calpain-type proteases, histone deacetylases and poly-ADP-ribose polymerase. An evaluation of the available literature reveals that a large group of patients suffering from hereditary photoreceptor degeneration carry mutations that are likely to trigger cGMP-dependent cell death, making this pathway a prime target for future therapy development. Finally, an outlook is given into technological and methodological developments that will with time likely contribute to a comprehensive overview over the entire metabolic complexity of photoreceptor cell death. Building on such developments, new imaging technology and novel biomarkers may be used to develop clinical test strategies, that fully consider the genetic heterogeneity of hereditary retinal degenerations, in order to facilitate clinical testing of novel treatment approaches.

Details

Authors
  • Michael Power
  • Soumyaparna Das
  • K. Schütze
  • Valeria Marigo
  • Per Ekström
  • François Paquet-Durand
Organisations
External organisations
  • University of Tübingen
  • University of Modena and Reggio Emilia
  • CellTool GmbH
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology

Keywords

  • Apoptosis, cGMP, Necroptosis, PARthanatos, PKG, Raman microscopy
Original languageEnglish
Article number100772
JournalProgress in Retinal and Eye Research
Volume74
Early online date2019 Jul 30
Publication statusPublished - 2020 Jan
Publication categoryResearch
Peer-reviewedYes