GSBS Student Publications

Student Author(s)

Aditya Venkatesh

GSBS Program

Interdisciplinary Graduate Program

UMMS Affiliation

Department of Ophthalmology; Gene Therapy Center

Date

4-1-2015

Document Type

Article

Medical Subject Headings

Adaptor Proteins, Signal Transducing; Animals; Apoptosis; Caspase 2; Cell Survival; Glucose; Insulin; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Mutant Strains; Models, Neurological; Multiprotein Complexes; NADP; PTEN Phosphohydrolase; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Retinitis Pigmentosa; Signal Transduction; TOR Serine-Threonine Kinases

Disciplines

Eye Diseases | Genetics and Genomics | Neuroscience and Neurobiology | Ophthalmology

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.

Rights and Permissions

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

DOI of Published Version

10.1172/JCI79766

Comments

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.

Related Resources

Link to Article in PubMed

Keywords

Genetics, Neuroscience, Ophthalmology

Journal Title

The Journal of clinical investigation

PubMed ID

25798619

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