Athanasiou Dimitra, Aguila Monica, Opefi Chikwado A, South Kieron, Bellingham James, Bevilacqua Dalila, Munro Peter M, Kanuga Naheed, Mackenzie Francesca E, Dubis Adam M, Georgiadis Anastasios, Graca Anna B, Pearson Rachael A, Ali Robin R, Sakami Sanae, Palczewski Krzysztof, Sherman Michael Y, Reeves Philip J, Cheetham Michael E
UCL Institute of Ophthalmology, 11-43 Bath Street, London, UK.
School of Biological Sciences, University of Essex, Wivenhoe Park, Essex, UK.
Hum Mol Genet. 2017 Jan 15;26(2):305-319. doi: 10.1093/hmg/ddw387.
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.
由遗传突变导致的蛋白质错误折叠会导致蛋白质功能丧失，并可能产生有毒的“功能获得”，例如导致色素性视网膜炎（RP）的显性P23H视紫红质突变。在此，我们测试了AMPK激活剂二甲双胍是否会影响P23H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P23H视紫红质的折叠和运输。在P23H RP动物模型中，二甲双胍治疗成功增强了P23H向视杆外段的运输，但这导致光感受器功能降低和光感受器细胞死亡增加。二甲双胍挽救的P23H视紫红质本质上仍然不稳定，并导致视杆外段结构不稳定性增加。这些数据表明，改善错误折叠的视紫红质突变体的运输不太可能成为一种实用的治疗方法，因为它们在外部段具有内在不稳定性和长半衰期，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蛋白质功能的潜力。
