Athanasiou, Dimitra and Aguila, Monica and Opefi, Chikwado A and South, Kieron and Bellingham, James and Bevilacqua, Dalila and Munro, Peter M and Kanuga, Naheed and Mackenzie, Francesca E and Dubis, Adam M and Georgiadis, Anastasios and Graca, Anna B and Pearson, Rachael A and Ali, Robin R and Sakami, Sanae and Palczewski, Krzysztof and Sherman, Michael Y and Reeves, Philip J and Cheetham, Michael E (2017) Rescue of mutant rhodopsin traffic by metformin-induced AMPK activation accelerates photoreceptor degeneration. Human Molecular Genetics, 26 (2). pp. 305-319. DOI https://doi.org/10.1093/hmg/ddw387
Athanasiou, Dimitra and Aguila, Monica and Opefi, Chikwado A and South, Kieron and Bellingham, James and Bevilacqua, Dalila and Munro, Peter M and Kanuga, Naheed and Mackenzie, Francesca E and Dubis, Adam M and Georgiadis, Anastasios and Graca, Anna B and Pearson, Rachael A and Ali, Robin R and Sakami, Sanae and Palczewski, Krzysztof and Sherman, Michael Y and Reeves, Philip J and Cheetham, Michael E (2017) Rescue of mutant rhodopsin traffic by metformin-induced AMPK activation accelerates photoreceptor degeneration. Human Molecular Genetics, 26 (2). pp. 305-319. DOI https://doi.org/10.1093/hmg/ddw387
Athanasiou, Dimitra and Aguila, Monica and Opefi, Chikwado A and South, Kieron and Bellingham, James and Bevilacqua, Dalila and Munro, Peter M and Kanuga, Naheed and Mackenzie, Francesca E and Dubis, Adam M and Georgiadis, Anastasios and Graca, Anna B and Pearson, Rachael A and Ali, Robin R and Sakami, Sanae and Palczewski, Krzysztof and Sherman, Michael Y and Reeves, Philip J and Cheetham, Michael E (2017) Rescue of mutant rhodopsin traffic by metformin-induced AMPK activation accelerates photoreceptor degeneration. Human Molecular Genetics, 26 (2). pp. 305-319. DOI https://doi.org/10.1093/hmg/ddw387
Abstract
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.
Item Type: | Article |
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Uncontrolled Keywords: | Animals; Humans; Mice; Rats; Retinitis Pigmentosa; Retinal Degeneration; Disease Models, Animal; Metformin; Rhodopsin; Protein Folding; Mutant Proteins; Photoreceptor Cells; Rod Cell Outer Segment; Transcriptional Activation; Retinal Rod Photoreceptor Cells; AMP-Activated Protein Kinases; Proteostasis Deficiencies |
Subjects: | Q Science > QH Natural history > QH301 Biology |
Divisions: | Faculty of Science and Health Faculty of Science and Health > Life Sciences, School of |
SWORD Depositor: | Unnamed user with email elements@essex.ac.uk |
Depositing User: | Unnamed user with email elements@essex.ac.uk |
Date Deposited: | 08 Mar 2017 10:04 |
Last Modified: | 30 Oct 2024 20:25 |
URI: | http://repository.essex.ac.uk/id/eprint/19218 |
Available files
Filename: ddw387.pdf
Licence: Creative Commons: Attribution 3.0