Rescue of mutant rhodopsin traffic by metformin-induced AMPK activation accelerates photoreceptor degeneration
| Autor: | 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 |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Photoreceptor Cells/drug effects
genetic structures Proteostasis Deficiencies/genetics Protein Folding/drug effects psychiatry Rats Disease Models Animal Mice Retinal Rod Photoreceptor Cells/drug effects Metformin/administration & dosage Retinitis Pigmentosa/drug therapy Animals Humans Rhodopsin/chemistry Transcriptional Activation/drug effects sense organs Mutant Proteins/genetics Rod Cell Outer Segment/drug effects Retinal Degeneration/drug therapy biological AMP-Activated Protein Kinases/biosynthesis |
| Zdroj: | Athanasiou, D, Aguila, M, Opefi, C A, South, K, Bellingham, J, Bevilacqua, D, Munro, P M, Kanuga, N, Mackenzie, F E, Dubis, A M, Georgiadis, A, Graca, A B, Pearson, R A, Ali, R R, Sakami, S, Palczewski, K, Sherman, M Y, Reeves, P J & Cheetham, M E 2017, ' Rescue of mutant rhodopsin traffic by metformin-induced AMPK activation accelerates photoreceptor degeneration ', Human Molecular Genetics, vol. 26, no. 2, pp. 305-319 . https://doi.org/10.1093/hmg/ddw387 |
| ISSN: | 0964-6906 |
| DOI: | 10.1093/hmg/ddw387 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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