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Rescue of mutant rhodopsin traffic by metformin-induced AMPK activation accelerates photoreceptor degeneration

Athanasiou, D and Aguila, M and Opefi, CA and South, K and Bellingham, J and Bevilacqua, D and Munro, PM and Kanuga, N and Mackenzie, FE and Dubis, AM and Georgiadis, A and Graca, AB and Pearson, RA and Ali, RR and Sakami, S and Palczewski, K and Sherman, MY and Reeves, PJ and Cheetham, ME (2017) 'Rescue of mutant rhodopsin traffic by metformin-induced AMPK activation accelerates photoreceptor degeneration.' Human Molecular Genetics, 26 (2). 305 - 319. ISSN 0964-6906

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Abstract

© The Author 2016. Published by Oxford University Press. All rights reserved. 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
Subjects: Q Science > QH Natural history > QH301 Biology
Divisions: Faculty of Science and Health > Biological Sciences, School of
Depositing User: Philip Reeves
Date Deposited: 08 Mar 2017 10:04
Last Modified: 17 Aug 2017 17:18
URI: http://repository.essex.ac.uk/id/eprint/19218

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