Nature communications · 2022
Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Senabouth Anne, Daniszewski Maciej, Lidgerwood Grace E, Liang Helena H, Hernández Damián, Mirzaei Mehdi, Keenan Stacey N, Zhang Ran, Han Xikun, Neavin Drew, Rooney Louise, Lopez Sanchez Maria Isabel G, Gulluyan Lerna, Paulo Joao A, Clarke Linda, Kearns Lisa S, Gnanasambandapillai Vikkitharan, Chan Chia-Ling, Nguyen Uyen, Steinmann Angela M, McCloy Rachael A, Farbehi Nona, Gupta Vivek K, Mackey David A, Bylsma Guy, Verma Nitin, MacGregor Stuart, Watt Matthew J, Guymer Robyn H, Powell Joseph E, Hewitt Alex W, Pébay Alice
Аннотация
There are currently no treatments for geographic atrophy, the advanced form of age-related macular degeneration. Hence, innovative studies are needed to model this condition and prevent or delay its progression. Induced pluripotent stem cells generated from patients with geographic atrophy and healthy individuals were differentiated to retinal pigment epithelium. Integrating transcriptional profiles of 127,659 retinal pigment epithelium cells generated from 43 individuals with geographic atrophy and 36 controls with genotype data, we identify 445 expression quantitative trait loci in cis that are asssociated with disease status and specific to retinal pigment epithelium subpopulations. Transcriptomics and proteomics approaches identify molecular pathways significantly upregulated in geographic atrophy, including in mitochondrial functions, metabolic pathways and extracellular cellular matrix reorganization. Five significant protein quantitative trait loci that regulate protein expression in the retinal pigment epithelium and in geographic atrophy are identified - two of which share variants with cis- expression quantitative trait loci, including proteins involved in mitochondrial biology and neurodegeneration. Investigation of mitochondrial metabolism confirms mitochondrial dysfunction as a core constitutive difference of the retinal pigment epithelium from patients with geographic atrophy. This study uncovers important differences in retinal pigment epithelium homeostasis associated with geographic atrophy.