Rescue of mutant rhodopsin traffic by metformin-induced AMPK activation accelerates photoreceptor degeneration.
Rescue of mutant rhodopsin traffic by metformin-induced AMPK activation accelerates photoreceptor degeneration.
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DOI：
10.1093/hmg/ddw387
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发表时间：
2017-01-15
影响因子：
3.5
通讯作者：
Cheetham ME
中科院分区：
文献类型：
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作者：
Athanasiou D;Aguila M;Opefi CA;South K;Bellingham J;Bevilacqua D;Munro PM;Kanuga N;Mackenzie FE;Dubis AM;Georgiadis A;Graca AB;Pearson RA;Ali RR;Sakami S;Palczewski K;Sherman MY;Reeves PJ;Cheetham ME
由遗传突变引起的蛋白质错误折叠导致蛋白质功能丧失和潜在的毒性“功能获得”，例如导致视网膜色素变性（RP）的显性P23 H视紫红质突变。在这里，我们测试了AMPK激活剂二甲双胍是否会影响P23 H视紫红质的合成和折叠。在细胞模型中，二甲双胍治疗改善了P23 H视紫红质折叠和运输。在P23 H RP的动物模型中，二甲双胍治疗成功地增强了P23 H向视杆细胞外节的运输，但这导致感光细胞功能降低和感光细胞死亡增加。二甲双胍拯救的P23 H视紫红质本质上仍然是不稳定的，并导致杆外节的结构不稳定性增加。这些数据表明，改善错误折叠视紫红质突变体的交通不太可能是一种实用的治疗方法，因为它们内在的不稳定性和外段的半衰期长，但也突出了通过AMPK改变翻译以改善其他蛋白质错误折叠疾病中的蛋白质功能的潜力。
Protein misfolding caused by inherited mutations leads to loss of protein function and potentially toxic ‘gain of function’, such as the dominant P23H rhodopsin mutation that causes retinitis pigmentosa (RP). Here, we tested whether the AMPK activator metformin could affect the P23H rhodopsin synthesis and folding. In cell models, metformin treatment improved P23H rhodopsin folding and traffic. In animal models of P23H RP, metformin treatment successfully enhanced P23H traffic to the rod outer segment, but this led to reduced photoreceptor function and increased photoreceptor cell death. The metformin-rescued P23H rhodopsin was still intrinsically unstable and led to increased structural instability of the rod outer segments. These data suggest that improving the traffic of misfolding rhodopsin mutants is unlikely to be a practical therapy, because of their intrinsic instability and long half-life in the outer segment, but also highlights the potential of altering translation through AMPK to improve protein function in other protein misfolding diseases.