دورية أكاديمية
AMPK Modulation Ameliorates Dominant Disease Phenotypes of CTRP5 Variant in Retinal Degeneration
| العنوان: | AMPK Modulation Ameliorates Dominant Disease Phenotypes of CTRP5 Variant in Retinal Degeneration |
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| المؤلفون: | 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, Sharp, Rachel C. |
| المصدر: | School of Graduate Studies Faculty Publications |
| بيانات النشر: | LSU Health Digital Scholar |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Medical Sciences, Medicine and Health Sciences, Neurosciences |
| الوصف: | 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. |
| نوع الوثيقة: | text |
| وصف الملف: | application/pdf |
| اللغة: | English |
| العلاقة: | https://digitalscholar.lsuhsc.edu/sogs_facpubs/41Test; https://digitalscholar.lsuhsc.edu/context/sogs_facpubs/article/1040/viewcontent/KautzmanG_AMPKModulationAmelio_2021.pdfTest |
| DOI: | 10.1038/s42003-021-02872-x |
| الإتاحة: | https://doi.org/10.1038/s42003-021-02872-xTest https://digitalscholar.lsuhsc.edu/sogs_facpubs/41Test https://digitalscholar.lsuhsc.edu/context/sogs_facpubs/article/1040/viewcontent/KautzmanG_AMPKModulationAmelio_2021.pdfTest |
| حقوق: | http://creativecommons.org/licenses/by/4.0Test/ |
| رقم الانضمام: | edsbas.AFD51A49 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s42003-021-02872-x |
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