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PKG activity causes photoreceptor cell death in two retinitis pigmentosa models

Paquet-Durand, Francois LU ; Hauck, Stefanie M.; van Veen, Theo LU ; Ueffing, Marius and Ekström, Per LU (2009) In Journal of Neurochemistry 108(3). p.796-810
Abstract
Photoreceptor degeneration in retinitis pigmentosa is one of the leading causes of hereditary blindness in the developed world. Although causative genetic mutations have been elucidated in many cases, the underlying neuronal degeneration mechanisms are still unknown. Here, we show that activation of cGMP-dependent protein kinase (PKG) hallmarks photoreceptor degeneration in rd1 and rd2 human homologous mouse models. When induced in wild-type retinae, PKG activity was both necessary and sufficient to trigger cGMP-mediated photoreceptor cell death. Target-specific, pharmacological inhibition of PKG activity in both rd1 and rd2 retinae strongly reduced photoreceptor cell death in organotypic retinal explants. Likewise, inhibition of PKG in... (More)
Photoreceptor degeneration in retinitis pigmentosa is one of the leading causes of hereditary blindness in the developed world. Although causative genetic mutations have been elucidated in many cases, the underlying neuronal degeneration mechanisms are still unknown. Here, we show that activation of cGMP-dependent protein kinase (PKG) hallmarks photoreceptor degeneration in rd1 and rd2 human homologous mouse models. When induced in wild-type retinae, PKG activity was both necessary and sufficient to trigger cGMP-mediated photoreceptor cell death. Target-specific, pharmacological inhibition of PKG activity in both rd1 and rd2 retinae strongly reduced photoreceptor cell death in organotypic retinal explants. Likewise, inhibition of PKG in vivo, using three different application paradigms, resulted in robust photoreceptor protection in the rd1 retina. These findings suggest a pivotal role for PKG activity in cGMP-mediated photoreceptor degeneration mechanisms and highlight the importance of PKG as a novel target for the pharmacological intervention in RP. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
rd1 mouse, nitric oxide, cGMP, calcium, cGK, retina
in
Journal of Neurochemistry
volume
108
issue
3
pages
796 - 810
publisher
Wiley-Blackwell
external identifiers
  • wos:000262348600024
  • scopus:58149333254
ISSN
1471-4159
DOI
10.1111/j.1471-4159.2008.05822.x
language
English
LU publication?
yes
id
697857a7-813f-475f-8ced-a3c9ee25130d (old id 1313325)
date added to LUP
2009-03-12 09:47:29
date last changed
2017-09-24 04:06:47
@article{697857a7-813f-475f-8ced-a3c9ee25130d,
  abstract     = {Photoreceptor degeneration in retinitis pigmentosa is one of the leading causes of hereditary blindness in the developed world. Although causative genetic mutations have been elucidated in many cases, the underlying neuronal degeneration mechanisms are still unknown. Here, we show that activation of cGMP-dependent protein kinase (PKG) hallmarks photoreceptor degeneration in rd1 and rd2 human homologous mouse models. When induced in wild-type retinae, PKG activity was both necessary and sufficient to trigger cGMP-mediated photoreceptor cell death. Target-specific, pharmacological inhibition of PKG activity in both rd1 and rd2 retinae strongly reduced photoreceptor cell death in organotypic retinal explants. Likewise, inhibition of PKG in vivo, using three different application paradigms, resulted in robust photoreceptor protection in the rd1 retina. These findings suggest a pivotal role for PKG activity in cGMP-mediated photoreceptor degeneration mechanisms and highlight the importance of PKG as a novel target for the pharmacological intervention in RP.},
  author       = {Paquet-Durand, Francois and Hauck, Stefanie M. and van Veen, Theo and Ueffing, Marius and Ekström, Per},
  issn         = {1471-4159},
  keyword      = {rd1 mouse,nitric oxide,cGMP,calcium,cGK,retina},
  language     = {eng},
  number       = {3},
  pages        = {796--810},
  publisher    = {Wiley-Blackwell},
  series       = {Journal of Neurochemistry},
  title        = {PKG activity causes photoreceptor cell death in two retinitis pigmentosa models},
  url          = {http://dx.doi.org/10.1111/j.1471-4159.2008.05822.x},
  volume       = {108},
  year         = {2009},
}