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.
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Miyagishima, Kiyoharu J.; Sharma, Ruchi; Nimmagadda, Malika; Clore-Gronenborn, Katharina; Qureshy, Zoya; Ortolan, Davide; Bose, Devika; Farnoodian, Mitra; Zhang, Congxiao; Fausey, Andrew; Sergeev, Yuri V.; Abu-Asab, Mones; Jun, Bokkyoo; Do, Khanh V.; Kautzman Guerin, Marie Audrey; Calandria, Jorgelina; George, Aman; Guan, Bin; Wan, Qin; and Sharp, Rachel C., "AMPK Modulation Ameliorates Dominant Disease Phenotypes of CTRP5 Variant in Retinal Degeneration" (2021). School of Graduate Studies Faculty Publications. 41.