Date of this Version
Article number 1360
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.
AMP-Activated Protein Kinases; Female; Humans; Male; Middle Aged; Phenotype; Retinal Degeneration
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., Guerin, M. K., Calandria, J., George, A., Guan, B., Wan, Q., Sharp, R. C., Cukras, C., Sieving, P. A., Hufnagel, R. B., Bazan, N., Boesze-Battaglia, K., Milller, S., & Bharti, K. (2021). AMPK Modulation Ameliorates Dominant Disease Phenotypes of CTRP5 Variant in Retinal Degeneration. Communications Biology, 4 (1), Article number 1360-. http://dx.doi.org/10.1038/s42003-021-02872-x
Date Posted: 08 December 2022
This document has been peer reviewed.