Skip Navigation



Human Molecular Genetics Advance Access published online on July 27, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi258
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
14/17/2547    most recent
ddi258v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Galy, A.
Right arrow Articles by Giangrande, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Galy, A.
Right arrow Articles by Giangrande, A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2005. Published by Oxford University Press. All rights reserved
Received March 8, 2005
Revised July 13, 2005

Article

Rhodopsin maturation defects induce photoreceptor death by apoptosis: A Fly model for RhodopsinPro23His Human Retinitis Pigmentosa

Anne Galy 1, Michel Joseph Roux 2, José Alain Sahel 2, Thierry Léveillard 2, and Angela Giangrande 3*

1 Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, BP 10142, 67404 Illkirch cedex, CU de Strasbourg, France; INSERM U592, Laboratoire de Physiopathologie Moléculaire et Cellulaire de la Rétine 75571 Paris Cedex 12, France
2 INSERM U592, Laboratoire de Physiopathologie Moléculaire et Cellulaire de la Rétine 75571 Paris Cedex 12, France
3 Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, BP 10142, 67404 Illkirch cedex, CU de Strasbourg, France

* To whom correspondence should be addressed.
Angela Giangrande, E-mail: angela{at}titus.u-strasbg.fr


  Abstract

rhodopsin mutations result in Autosomal Dominant Retinitis Pigmentosa (ADRP), the most frequent being Proline 23 substitution by Histidine (RhoP23H). Although cellular and rodent animal models have been developed, the pathogenic mechanisms leading to RhoP23H induced cell death are still poorly understood. To this purpose, we have used a Drosophila model by introducing a mutation in the fly rhodopsin-1 gene (Rh1P37H) that corresponds to human RhoP23H. Rh1P37H transgenic flies show dominant photoreceptor degeneration that mimics age-, light-dependent and progressive ADRP. Moreover, we clarify the pathogenic mechanism of Rh1P37H mutation, which acts as an antimorph. First, we show dual localisation of mutant Rhodopsin, most Rh1P37H accumulating in endoplasmic reticulum. Second, expression of mutant, mislocalized, Rhodopsin leads to cytotoxicity, via the activation of two stress-specific MAPK, p38 and JNK, which are known to control stress-induced apoptosis. In Rh1P37H flies visual loss and degeneration are indeed accompanied by apoptotic features and prevented by expression of p35 apoptosis inhibitor. Finally, we show for the first time that, properly localized, mutant, Rhodopsin is active.

Thus, the development of a fly model that faithfully reproduces the human disease sheds light onto the molecular defects causing ADRP thereby making it possible to devise potential therapeutic approaches.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Proc. Natl. Acad. Sci. USAHome page
R. Datta, A. Waheed, G. Bonapace, G. N. Shah, and W. S. Sly
Pathogenesis of retinitis pigmentosa associated with apoptosis-inducing mutations in carbonic anhydrase IV
PNAS, March 3, 2009; 106(9): 3437 - 3442.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
B. M. Tam and O. L. Moritz
Dark Rearing Rescues P23H Rhodopsin-Induced Retinal Degeneration in a Transgenic Xenopus laevis Model of Retinitis Pigmentosa: A Chromophore-Dependent Mechanism Characterized by Production of N-Terminally Truncated Mutant Rhodopsin
J. Neurosci., August 22, 2007; 27(34): 9043 - 9053.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.