title: Reprogramming towards anabolism impedes degeneration in a preclinical model of retinitis pigmentosa.
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/H620Qpreclinical 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.
authors: 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.|Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USA.|Shanxi Eye Hospital, affiliated with Shanxi Medical University, Xinghualing, Taiyuan, Shanxi, China.
authors: Lijuan
authors: L
authors: Zhang
authors: 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.|Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USA.
authors: Sally
authors: S
authors: Justus
authors: 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.|Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USA.|Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Yu
authors: Y
authors: Xu
authors: 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.|Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USA.
authors: Tamara
authors: T
authors: Pluchenik
authors: 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.|Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USA.
authors: Chun-Wei
authors: CW
authors: Hsu
authors: 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.|Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USA.|Tianjin Medical University Eye Hospital, Tianjin, China.
authors: Jin
authors: J
authors: Yang
authors: Department of Biostatistics, Mailman School of Public Health, Columbia University Medical Center, New York, USA.
authors: Jimmy K
authors: JK
authors: Duong
authors: 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.
authors: Chyuan-Sheng
authors: CS
authors: Lin
authors: Shanxi Eye Hospital, affiliated with Shanxi Medical University, Xinghualing, Taiyuan, Shanxi, China.
authors: Yading
authors: Y
authors: Jia
authors: Department of Pediatrics and Neurology, University of Iowa, Iowa City, IA.
authors: Alexander G
authors: AG
authors: Bassuk
authors: Omics Laboratory, University of Iowa, Iowa City, IA, USA.|Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA.
authors: Vinit B
authors: VB
authors: Mahajan
authors: 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.|Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USA.
authors: Stephen H
authors: SH
authors: Tsang
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics; D065150:Cellular Reprogramming / Q000235:genetics; D000071700:Cone-Rod Dystrophies / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology; D008660:Metabolism / Q000235:genetics; D051379:Mice; D010786:Photoreceptor Cells / Q000378:metabolism / Q000473:pathology*; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases