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Activated mTORC1 promotes long-term cone survival in retinitis pigmentosa mice
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
 
ID 2999594
Author(s) Venkatesh, A.; Ma, S.; Le, Y. Z.; Hall, M. N.; Rüegg, M. A.; Punzo, C.
Author(s) at UniBasel Hall, Michael N.
Rüegg, Markus A.
Year 2015
Title Activated mTORC1 promotes long-term cone survival in retinitis pigmentosa mice
Journal Journal of Clinical Investigation
Volume 125
Number 4
Pages / Article-Number 1446-1458
Abstract

Retinitis pigmentosa (RP) is an inherited photoreceptor degenerative disorder that results in blindness. The disease is often caused by mutations in genes that are specific to rod photoreceptors; however, blindness results from the secondary loss of cones by a still unknown mechanism. Here, we demonstrated that the mammalian target of rapamycin complex 1 (mTORC1) is required to slow the progression of cone death during disease and that constitutive activation of mTORC1 in cones is sufficient to maintain cone function and promote long-term cone survival. Activation of mTORC1 in cones enhanced glucose uptake, retention, and utilization, leading to increased levels of the key metabolite NADPH. Moreover, cone death was delayed in the absence of the NADPH-sensitive cell death protease caspase 2, supporting the contribution of reduced NADPH in promoting cone death. Constitutive activation of mTORC1 preserved cones in 2 mouse models of RP, suggesting that the secondary loss of cones is caused mainly by metabolic deficits and is independent of a specific rod-associated mutation. Together, the results of this study address a longstanding question in the field and suggest that activating mTORC1 in cones has therapeutic potential to prolong vision in RP.

Publisher American Society for Clinical Investigation
ISSN/ISBN 0021-9738 ; 1558-8238
edoc-URL http://edoc.unibas.ch/dok/A6373477
Full Text on edoc Available
Digital Object Identifier DOI 10.1172/JCI79766
PubMed ID http://www.ncbi.nlm.nih.gov/pubmed/25798619
ISI-Number WOS:000352248600012
Document type (ISI) Journal Article
 
   

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