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Hum Mol Genet. 2016 Oct 1;25(19):4244-4255. doi: 10.1093/hmg/ddw256. Epub 2016 Aug 11.

Reprogramming towards anabolism impedes degeneration in a preclinical model of retinitis pigmentosa.

Zhang L1,2,3, Justus S1,2, Xu Y1,2,4, Pluchenik T1,2, Hsu CW1,2, Yang J1,2,5, Duong JK6, Lin CS7, Jia Y3, Bassuk AG8, Mahajan VB9,10, Tsang SH11,2.

Author information

1
Barbara & Donald Jonas Stem Cell & Regenerative Medicine Laboratory, and Bernard & Shirlee Brown Glaucoma Laboratory, Departments of Ophthalmology and Pathology & Cell Biology, Institute of Human Nutrition, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
2
Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USA.
3
Shanxi Eye Hospital, affiliated with Shanxi Medical University, Xinghualing, Taiyuan, Shanxi, China.
4
Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
5
Tianjin Medical University Eye Hospital, Tianjin, China.
6
Department of Biostatistics, Mailman School of Public Health, Columbia University Medical Center, New York, USA.
7
Department of Pathology and Cell Biology, Transgenic Animal Facility, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
8
Department of Pediatrics and Neurology, University of Iowa, Iowa City, IA.
9
Omics Laboratory, University of Iowa, Iowa City, IA, USA.
10
Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA.
11
Barbara & Donald Jonas Stem Cell & Regenerative Medicine Laboratory, and Bernard & Shirlee Brown Glaucoma Laboratory, Departments of Ophthalmology and Pathology & Cell Biology, Institute of Human Nutrition, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA sht2@columbia.edu.

Abstract

Retinitis pigmentosa (RP) is an incurable neurodegenerative condition featuring photoreceptor death that leads to blindness. Currently, there is no approved therapeutic for photoreceptor degenerative conditions like RP and atrophic age-related macular degeneration (AMD). Although there are promising results in human gene therapy, RP is a genetically diverse disorder, such that gene-specific therapies would be practical in a small fraction of patients with RP. Here, we explore a non-gene-specific strategy that entails reprogramming photoreceptors towards anabolism by upregulating the mechanistic target of rapamycin (mTOR) pathway. We conditionally ablated the tuberous sclerosis complex 1 (Tsc1) gene, an mTOR inhibitor, in the rods of the Pde6bH620Q/H620Q preclinical RP mouse model and observed, functionally and morphologically, an improvement in the survival of rods and cones at early and late disease stages. These results elucidate the ability of reprogramming the metabolome to slow photoreceptor degeneration. This strategy may also be applicable to a wider range of neurodegenerative diseases, as enhancement of nutrient uptake is not gene-specific and is implicated in multiple pathologies. Enhancing anabolism promoted neuronal survival and function and could potentially benefit a number of photoreceptor and other degenerative conditions.

PMID:
27516389
PMCID:
PMC5291198
DOI:
10.1093/hmg/ddw256
[Indexed for MEDLINE]
Free PMC Article

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