Loading...
Thumbnail Image
Publication

Activated mTORC1 promotes long-term cone survival in retinitis pigmentosa mice

Venkatesh, Aditya
Ma, Shan
Le, Yun Z.
Hall, Michael N.
Ruegg, Markus A.
Punzo, Claudio
Citations
Altmetric:
Student Authors
Aditya Venkatesh
Faculty Advisor
Academic Program
Document Type
Journal Article
Publication Date
2015-04-01
Keywords
Subject Area
Embargo Expiration Date
Link to Full Text
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.

Source

J Clin Invest. 2015 Apr;125(4):1446-58. doi: 10.1172/JCI79766. Epub 2015 Mar 23. Link to article on publisher's site

Year of Medical School at Time of Visit
Sponsors
Dates of Travel
DOI
10.1172/JCI79766
PubMed ID
25798619
Other Identifiers
Notes
Funding and Acknowledgements
Corresponding Author
Related Resources
Related Resources
Repository Citation
Rights
Copyright © 2015, The American Society for Clinical Investigation. Publisher PDF posted as allowed by the publisher's author rights policy at http://content-assets.jci.org/admin/forms/jcicopyright.pdf.
Distribution License