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

Author:

Miyagishima Kiyoharu J.ORCID,Sharma Ruchi,Nimmagadda Malika,Clore-Gronenborn Katharina,Qureshy Zoya,Ortolan DavideORCID,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,Sharp Rachel C.ORCID,Cukras Catherine,Sieving Paul A.ORCID,Hufnagel Robert B.,Bazan Nicolas G.ORCID,Boesze-Battaglia Kathleen,Miller Sheldon,Bharti KapilORCID

Abstract

AbstractLate-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.

Publisher

Springer Science and Business Media LLC

Subject

General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)

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