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Cellular mechanisms of hereditary photoreceptor degeneration – Focus on cGMP

Power, Michael ; Das, Soumyaparna ; Schütze, K. ; Marigo, Valeria ; Ekström, Per LU and Paquet-Durand, François LU (2019) In Progress in Retinal and Eye Research
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... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
Apoptosis, cGMP, Necroptosis, PARthanatos, PKG, Raman microscopy
in
Progress in Retinal and Eye Research
article number
100772
publisher
Elsevier
external identifiers
  • scopus:85070495842
ISSN
1350-9462
DOI
10.1016/j.preteyeres.2019.07.005
language
English
LU publication?
yes
id
5f5befff-c3ae-4c16-9996-e1bd57607415
date added to LUP
2019-08-27 09:29:17
date last changed
2020-01-22 07:45:11
@article{5f5befff-c3ae-4c16-9996-e1bd57607415,
  abstract     = {<p>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 Ca<sup>2+</sup>-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 Ca<sup>2+</sup>-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.</p>},
  author       = {Power, Michael and Das, Soumyaparna and Schütze, K. and Marigo, Valeria and Ekström, Per and Paquet-Durand, François},
  issn         = {1350-9462},
  language     = {eng},
  month        = {07},
  publisher    = {Elsevier},
  series       = {Progress in Retinal and Eye Research},
  title        = {Cellular mechanisms of hereditary photoreceptor degeneration – Focus on cGMP},
  url          = {http://dx.doi.org/10.1016/j.preteyeres.2019.07.005},
  doi          = {10.1016/j.preteyeres.2019.07.005},
  year         = {2019},
}