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
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...
December 9, 2021: Communications Biology