{"doi":"10.1038/s42003-021-02872-x","title":"AMPK modulation ameliorates dominant disease phenotypes of CTRP5 variant in retinal degeneration","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.","journal":"Communications Biology","year":2021,"id":165550,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":36,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9491,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":294128,"name":"Ruchi Sharma","orcid":"0000-0002-2138-6462","position":1,"is_corresponding":false},{"id":690107,"name":"Malika Nimmagadda","orcid":null,"position":2,"is_corresponding":false},{"id":311547,"name":"Katharina Clore-Gronenborn","orcid":"0000-0002-7132-3152","position":3,"is_corresponding":false},{"id":265965,"name":"Zoya Qureshy","orcid":"0000-0003-3793-5400","position":4,"is_corresponding":false},{"id":689285,"name":"Davide Ortolan","orcid":"0000-0002-8236-9391","position":5,"is_corresponding":false},{"id":296474,"name":"Devika Bose","orcid":null,"position":6,"is_corresponding":false},{"id":689286,"name":"Mitra Farnoodian","orcid":"0000-0001-6990-8111","position":7,"is_corresponding":false},{"id":286496,"name":"Congxiao Zhang","orcid":"0009-0006-3298-4616","position":8,"is_corresponding":false},{"id":690108,"name":"Andrew Fausey","orcid":null,"position":9,"is_corresponding":false},{"id":99002,"name":"Yuri V. 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