Excessive activation of poly(ADP-ribose) polymerase contributes to inherited photoreceptor degeneration in the retinal degeneration 1 mouse.
(2007) In The Journal of Neuroscience 27(38). p.10311-10319- Abstract
- Retinitis pigmentosa (RP) is an inherited blinding disease for which there is no treatment available. It is characterized by a progressive and neurodegenerative loss of photoreceptors but the underlying mechanisms are poorly understood. Excessive activation of the enzyme poly(ADP-ribose) polymerase (PARP) has recently been shown to be involved in several neuropathologies. To investigate the possible role of PARP in retinal photoreceptor degeneration, we used the retinal degeneration 1 (rd1) mouse RP model to study PARP expression, PARP activity, and to test the effects of PARP inhibition on photoreceptor viability. PARP expression was found to be equal between rd1 and wild-type counterpart retinas. In contrast to this, a dramatic increase... (More)
- Retinitis pigmentosa (RP) is an inherited blinding disease for which there is no treatment available. It is characterized by a progressive and neurodegenerative loss of photoreceptors but the underlying mechanisms are poorly understood. Excessive activation of the enzyme poly(ADP-ribose) polymerase (PARP) has recently been shown to be involved in several neuropathologies. To investigate the possible role of PARP in retinal photoreceptor degeneration, we used the retinal degeneration 1 (rd1) mouse RP model to study PARP expression, PARP activity, and to test the effects of PARP inhibition on photoreceptor viability. PARP expression was found to be equal between rd1 and wild-type counterpart retinas. In contrast to this, a dramatic increase in both PARP activity per se and PARP product formation was detected by in situ assays in rd1 photoreceptors actively undergoing cell death. Furthermore, PARP activity colabeled with oxidatively damaged DNA and nuclear translocation of AIF (apoptosis-inducing factor), suggesting activation of PARP as a bridge between these events in the degenerating photoreceptors. The PARP-specific inhibitor PJ34 [N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide center dot HCl] reduced the number of cells exhibiting death markers in a short-term retinal culture paradigm, a protective effect that was translated into an increased number of surviving photoreceptors when the inhibitor was used in a long-term culture setting. Our results thus demonstrate an involvement of PARP activity in rd1 photoreceptor cell death, which could have a bearing on the understanding of neurodegenerations as such. The findings also suggest that the therapeutical possibilities of PARP inhibition should include retinal diseases like RP. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/607655
- author
- Paquet-Durand, Francois LU ; Silva, José LU ; Talukdar, Tanuja LU ; Johnson, Leif LU ; Azadi, Seifollah LU ; van Veen, Theo LU ; Ueffing, Marius ; Hauck, Stefanie M and Ekström, Per LU
- organization
- publishing date
- 2007
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- blindnessapoptosisneuroprotection, necrosis, poly( ADP), neuropathology, ribosylation
- in
- The Journal of Neuroscience
- volume
- 27
- issue
- 38
- pages
- 10311 - 10319
- publisher
- Society for Neuroscience
- external identifiers
-
- wos:000249584100026
- scopus:34548847441
- pmid:17881537
- ISSN
- 1529-2401
- DOI
- 10.1523/JNEUROSCI.1514-07.2007
- language
- English
- LU publication?
- yes
- id
- 9036861c-8140-41e0-970e-c4e7607aa26a (old id 607655)
- alternative location
- http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17881537&dopt=Abstract
- date added to LUP
- 2016-04-01 16:20:21
- date last changed
- 2023-09-18 16:40:48
@article{9036861c-8140-41e0-970e-c4e7607aa26a,
abstract = {{Retinitis pigmentosa (RP) is an inherited blinding disease for which there is no treatment available. It is characterized by a progressive and neurodegenerative loss of photoreceptors but the underlying mechanisms are poorly understood. Excessive activation of the enzyme poly(ADP-ribose) polymerase (PARP) has recently been shown to be involved in several neuropathologies. To investigate the possible role of PARP in retinal photoreceptor degeneration, we used the retinal degeneration 1 (rd1) mouse RP model to study PARP expression, PARP activity, and to test the effects of PARP inhibition on photoreceptor viability. PARP expression was found to be equal between rd1 and wild-type counterpart retinas. In contrast to this, a dramatic increase in both PARP activity per se and PARP product formation was detected by in situ assays in rd1 photoreceptors actively undergoing cell death. Furthermore, PARP activity colabeled with oxidatively damaged DNA and nuclear translocation of AIF (apoptosis-inducing factor), suggesting activation of PARP as a bridge between these events in the degenerating photoreceptors. The PARP-specific inhibitor PJ34 [N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide center dot HCl] reduced the number of cells exhibiting death markers in a short-term retinal culture paradigm, a protective effect that was translated into an increased number of surviving photoreceptors when the inhibitor was used in a long-term culture setting. Our results thus demonstrate an involvement of PARP activity in rd1 photoreceptor cell death, which could have a bearing on the understanding of neurodegenerations as such. The findings also suggest that the therapeutical possibilities of PARP inhibition should include retinal diseases like RP.}},
author = {{Paquet-Durand, Francois and Silva, José and Talukdar, Tanuja and Johnson, Leif and Azadi, Seifollah and van Veen, Theo and Ueffing, Marius and Hauck, Stefanie M and Ekström, Per}},
issn = {{1529-2401}},
keywords = {{blindnessapoptosisneuroprotection; necrosis; poly( ADP); neuropathology; ribosylation}},
language = {{eng}},
number = {{38}},
pages = {{10311--10319}},
publisher = {{Society for Neuroscience}},
series = {{The Journal of Neuroscience}},
title = {{Excessive activation of poly(ADP-ribose) polymerase contributes to inherited photoreceptor degeneration in the retinal degeneration 1 mouse.}},
url = {{http://dx.doi.org/10.1523/JNEUROSCI.1514-07.2007}},
doi = {{10.1523/JNEUROSCI.1514-07.2007}},
volume = {{27}},
year = {{2007}},
}