Abstract
Retinitis pigmentosa (RP) is a neurodegenerative disorder that causes irreversible vision loss in over 1.5 million individuals world-wide. The genetic heterogeneity of RP necessitates a broad therapy that is able to provide treatment in a gene- and mutation- non-specific manner. In this study, we identify the therapeutic benefits of metabolic reprogramming by targeting pyruvate kinase M2 (PKM2) in a Pde6β preclinical model of RP. The genetic contributions of PKM2 inhibition in retinal degeneration were evaluated through histology and electroretinogram (ERG) followed by a statistical analysis using a linear regression model. Notably, PKM2 ablation resulted in thicker retinal layers in Pde6β-mutated mice as compared to the controls, suggesting greater photoreceptor survival. Consistent with these anatomical findings, ERG analyses revealed that the maximum b-wave is on average greater in Pkm2 knockout mice than in mice with intact Pkm2, indicating enhanced photoreceptor function. These rescue phenotypes from Pkm2 ablation in a preclinical model of RP indicate that a metabolome reprogramming may be useful in treating RP.
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All data in this manuscript are available for share. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
Jonas Children’s Vision Care and Bernard & Shirlee Brown Glaucoma Laboratory are supported by the National Institutes of Health [P30EY019007, R01EY018213, R01EY026682, R24EY027285, R24 EY28758-U01EY030580, National Cancer Institute Core [5P30CA013696], Foundation Fighting Blindness [TA-NMT-0116-0692-COLU], the Research to Prevent Blindness (RPB) Physician-Scientist Award, and unrestricted funds from RPB, New York, NY, USA. S.H.T. is a member of the RD-CURE Consortium and is supported by Kobi and Nancy Karp, the Crowley Family Fund, the Rosenbaum Family Foundation, the Tistou and Charlotte Kerstan Foundation, the Schneeweiss Stem Cell Fund, New York State [C029572], and the Gebroe Family Foundation.
Funding
Funding for this research was supported by the Global Ophthalmology Awards Program (GOAP), a Bayer-sponsored initiative committed to supporting ophthalmic research across the world. The Jonas Children’s Vision Care and Bernard & Shirlee Brown Glaucoma Laboratory are supported by the National Institutes of Health [P30EY019007, R01EY018213, R01EY024698, R01EY026682, R24EY027285, U01EY030580; R24 EY28758], National Cancer Institute Core [5P30CA013696], Foundation Fighting Blindness [TA-NMT-0116-0692-COLU], the Research to Prevent Blindness (RPB) Physician-Scientist Award, and unrestricted funds from RPB, New York, NY, USA. S.H.T. is a member of the RD-CURE Consortium and is supported by Kobi and Nancy Karp, the Crowley Family Fund, the Rosenbaum Family Foundation, the Tistou and Charlotte Kerstan Foundation, the Schneeweiss Stem Cell Fund, New York State [C029572], and the Gebroe Family Foundation.
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EZ and JR analyzed and interpreted the data and drafted the manuscript. SR and JO were major contributors in the critical revision of the manuscript. EZ, CH, XC, NW, and TY performed analysis of the variant effects of Pkm2 ablation on retinal morphology and function and were contributors to figure production. JR conducted the background literature review, provided figure descriptions and contributed to figure production. SHT was involved in the conception of this work and revising the manuscript for content. All authors read and approved the final manuscript.
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All experiments were approved by the Columbia University Institutional Animal Care and Use Committee (IACUC) prior to the start of the study. All mice were used and maintained in accordance with the Statement for the Use of Animals in Ophthalmic and Vision Research of the Association for Research in Vision and Ophthalmology and the Policy for the Use of Animals in Neuroscience Research of the Society for Neuroscience.
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Zhang, E., Ryu, J., Levi, S.R. et al. PKM2 ablation enhanced retinal function and survival in a preclinical model of retinitis pigmentosa. Mamm Genome 31, 77–85 (2020). https://doi.org/10.1007/s00335-020-09837-1
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DOI: https://doi.org/10.1007/s00335-020-09837-1