AMPK modulation ameliorates dominant disease phenotypes of CTRP5 variant in retinal degeneration.
AMPK modulation ameliorates dominant disease phenotypes of CTRP5 variant in retinal degeneration.
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DOI：
10.1038/s42003-021-02872-x
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发表时间：
2021-12-09
影响因子：
5.9
通讯作者：
Bharti K
中科院分区：
文献类型：
--
作者：
Miyagishima KJ;Sharma R;Nimmagadda M;Clore-Gronenborn K;Qureshy Z;Ortolan D;Bose D;Farnoodian M;Zhang C;Fausey A;Sergeev YV;Abu-Asab M;Jun B;Do KV;Kautzman Guerin MA;Calandria J;George A;Guan B;Wan Q;Sharp RC;Cukras C;Sieving PA;Hufnagel RB;Bazan NG;Boesze-Battaglia K;Miller S;Bharti K
迟发性视网膜变性（L - ORD）是一种由CTRP5的错义替换引起的常染色体显性遗传病。其独特的临床特征包括视网膜色素上皮（RPE）下沉积物、脉络膜新生血管形成以及RPE萎缩。在来自L - ORD患者的诱导多能干细胞衍生的RPE（L - ORD - iRPE）中，我们发现显性致病的CTRP5变异体导致CTRP5分泌减少。计算机模拟表明突变型CTRP5与脂联素受体1（ADIPOR1）的结合力降低。在ADIPOR1的下游，AMPK的持续激活使其对AMP/ATP比值的变化不敏感，从而导致脂质代谢缺陷、神经保护素D1（NPD1）分泌减少、线粒体呼吸降低以及ATP产生减少。这些代谢缺陷导致RPE下沉积物的积累，并使L - ORD - iRPE易于去分化。用野生型CTRP5对L - ORD - iRPE进行基因增强，或者用二甲双胍调节AMPK，可使L - ORD - iRPE对细胞能量状态的变化重新敏感，从而缓解疾病的细胞表型。我们的数据揭示了CTRP5突变显性作用的机制，并为L - ORD患者提供了潜在的治疗策略。
宫城岛等人研究了迟发性视网膜变性（L - ORD）中突变型CTRP5功能的病理机制。利用人诱导多能干细胞衍生的RPE细胞，他们证明在L - ORD的iRPE中，AMPK的持续性激活破坏了细胞代谢/能量稳态，改变了顶端/基底的血管内皮生长因子（VEGF）分泌，而二甲双胍治疗纠正了这些相关表型。
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. Miyagishima et al. investigate the pathological mechanisms underlying mutant CTRP5 function in late-onset retinal degeneration (L-ORD). With human iPSC-derived RPE cells, they demonstrate that in L-ORD iRPE, constitutive activation of AMPK disrupts cellular metabolism/energy homoeostasis, changes apical/basal VEGF secretion, and Metformin treatment corrects these associated phenotypes.
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