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Miyagishima KJ, Sharma R, Nimmagadda M, et al. AMPK modulation ameliorates dominant disease phenotypes of CTRP5 variant in retinal degeneration. Commun Biol. 2021;4(1):1360doi: 10.1038/s42003-021-02872-x.
Miyagishima, K. J., Sharma, R., Nimmagadda, M., Clore-Gronenborn, K., Qureshy, Z., Ortolan, D., Bose, D., Farnoodian, M., Zhang, C., Fausey, A., Sergeev, Y. V., Abu-Asab, M., Jun, B., Do, K. V., Kautzman Guerin, M. A., Calandria, J., George, A., Guan, B., Wan, Q., Sharp, R. C., Cukras, C., Sieving, P. A., Hufnagel, R. B., Bazan, N. G., Boesze-Battaglia, K., Miller, S., & Bharti, K. (2021). AMPK modulation ameliorates dominant disease phenotypes of CTRP5 variant in retinal degeneration. Communications biology, 4(1), 1360. https://doi.org/10.1038/s42003-021-02872-x
Miyagishima, Kiyoharu J, et al. "AMPK modulation ameliorates dominant disease phenotypes of CTRP5 variant in retinal degeneration." Communications biology vol. 4,1 (2021): 1360. doi: https://doi.org/10.1038/s42003-021-02872-x
Miyagishima KJ, Sharma R, Nimmagadda M, Clore-Gronenborn K, Qureshy Z, Ortolan D, Bose D, Farnoodian M, Zhang C, Fausey A, Sergeev YV, Abu-Asab M, Jun B, Do KV, Kautzman Guerin MA, Calandria J, George A, Guan B, Wan Q, Sharp RC, Cukras C, Sieving PA, Hufnagel RB, Bazan NG, Boesze-Battaglia K, Miller S, Bharti K. AMPK modulation ameliorates dominant disease phenotypes of CTRP5 variant in retinal degeneration. Commun Biol. 2021 Dec 09;4(1):1360. doi: 10.1038/s42003-021-02872-x. PMID: 34887495; PMCID: PMC8660775.
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Commun Biol. 2021 Dec 09;4(1):1360. doi: 10.1038/s42003-021-02872-x.

AMPK modulation ameliorates dominant disease phenotypes of CTRP5 variant in retinal degeneration.

Communications biology

Kiyoharu J Miyagishima, Ruchi Sharma, Malika Nimmagadda, Katharina Clore-Gronenborn, Zoya Qureshy, Davide Ortolan, Devika Bose, Mitra Farnoodian, Congxiao Zhang, Andrew Fausey, Yuri V Sergeev, Mones Abu-Asab, Bokkyoo Jun, Khanh V Do, Marie-Audrey Kautzman Guerin, Jorgelina Calandria, Aman George, Bin Guan, Qin Wan, Rachel C Sharp, Catherine Cukras, Paul A Sieving, Robert B Hufnagel, Nicolas G Bazan, Kathleen Boesze-Battaglia, Sheldon Miller, Kapil Bharti

Affiliations

  1. Section on Epithelial and Retinal Physiology and Disease, NEI, NIH, Bethesda, MD, 20892, USA.
  2. Ocular and Stem Cell Translational Research Section, NEI, NIH, Bethesda, MD, 20892, USA.
  3. Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, MD, 20892, USA.
  4. Section of Histopathology, National Eye Institute, NIH, Bethesda, MD, 20892, USA.
  5. Neuroscience Center of Excellence, Louisiana State University Health, New Orleans, LA, 70112, USA.
  6. Medical Genetics and Ophthalmic Genomics Unit, NEI, NIH, Bethesda, MD, 20892, USA.
  7. Department of Biochemistry University of Pennsylvania, 240 South 40th Street, Levy Building, Room 515, Philadelphia, PA, 19104, USA.
  8. Division of Epidemiology and Clinical Applications and Ophthalmic Genetics and Visual Function Branch, NEI, NIH, Bethesda, MD, 20892, USA.
  9. Section for Translation Research in Retinal and Macular Degeneration, NEI, NIH, Bethesda, MD, 20892, USA.
  10. Ocular and Stem Cell Translational Research Section, NEI, NIH, Bethesda, MD, 20892, USA. [email protected].

PMID: 34887495 PMCID: PMC8660775 DOI: 10.1038/s42003-021-02872-x

Abstract

Late-onset retinal degeneration (L-ORD) is an autosomal dominant disorder caused by a missense substitution in CTRP5. Distinctive clinical features include sub-retinal pigment epithelium (RPE) deposits, choroidal neovascularization, and RPE atrophy. In induced pluripotent stem cells-derived RPE from L-ORD patients (L-ORD-iRPE), we show that the dominant pathogenic CTRP5 variant leads to reduced CTRP5 secretion. In silico modeling suggests lower binding of mutant CTRP5 to adiponectin receptor 1 (ADIPOR1). Downstream of ADIPOR1 sustained activation of AMPK renders it insensitive to changes in AMP/ATP ratio resulting in defective lipid metabolism, reduced Neuroprotectin D1(NPD1) secretion, lower mitochondrial respiration, and reduced ATP production. These metabolic defects result in accumulation of sub-RPE deposits and leave L-ORD-iRPE susceptible to dedifferentiation. Gene augmentation of L-ORD-iRPE with WT CTRP5 or modulation of AMPK, by metformin, re-sensitize L-ORD-iRPE to changes in cellular energy status alleviating the disease cellular phenotypes. Our data suggests a mechanism for the dominant behavior of CTRP5 mutation and provides potential treatment strategies for L-ORD patients.

© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

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