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

Athanasiou, Dimitra; Aguilà, Mònica; Opefi, Chikwado A.; South, Kieron; Bellingham, James; Bevilacqua, Dalila; Munro, Peter; Kanuga, Naheed; Mackenzie, Francesca E.; Dubis, Adam M.; Georgiadis, Anastasios; Graca, Anna B.; Pearson, R. A.; Ali, Robin R.; Sakami, Sanae; Palczewski, Krzysztof; Sherman, Michael Y.; Reeves, Philip J.; Cheetham, Michael E.

doi:10.1093/hmg/ddw387

Cited by 39 publications

(55 citation statements)

References 68 publications

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“…However, there are likely to be limitations. In a recent study, metformin was used to protect photoreceptors from a misfolded protein response caused by overexpressing a mutant opsin protein (Opsin P23H ) in transgenic rats (39). In contrast to our results, the authors found that metformin did not slow rod degeneration in these animals.…”

Section: Discussioncontrasting

confidence: 99%

Stimulation of AMPK prevents degeneration of photoreceptors and the retinal pigment epithelium

Kong

Wang

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

119

112

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Retinal degenerative diseases are generally characterized by a permanent loss of light-sensitive retinal neurons known as photoreceptors, or their support cells, the retinal pigmented epithelium (RPE). Metabolic dysfunction has been implicated as a common mechanism of degeneration. In this study, we used the drug metformin in a gain-of-function approach to activate adenosine monophosphate-activated protein kinase (AMPK). We found that treatment protected photoreceptors and the RPE from acute injury and delayed inherited retinal degeneration. Protection was associated with decreased oxidative stress, decreased DNA damage, and increased mitochondrial energy production. To determine whether protection was a local or a systemic effect of metformin, we used AMPK retinal knockout mice and found that local expression of AMPK catalytic subunit α2 was required for metformin-induced protection. Our data demonstrate that increasing the activity of AMPK in retinal neurons or glia can delay or prevent degeneration of photoreceptors and the RPE from multiple types of cell-death triggers.

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Section: Discussioncontrasting

confidence: 99%

Stimulation of AMPK prevents degeneration of photoreceptors and the retinal pigment epithelium

Kong

Wang

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

119

112

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“…The P23H-1 transgenic rat shows PERK activation ( 5 ) and undergoes fast retinal degeneration with 25% photoreceptor loss by postnatal day 15 (P15) compared with wild-type (WT) Sprague Dawley (SD) rats, which provides a rapid and robust model for the assessment of the ability of drugs to affect photoreceptor survival ( 22 , 23 , 28 , 29 ). GSK2606414A is a potent and selective inhibitor of PERK, it is functionally active in cells, and inhibits PERK with a selectivity of >385 fold over other eIF2α kinases and a panel of 294 kinases, and has excellent central nervous system (CNS) penetration following oral dosing ( 14 , 30 ).…”

Section: Resultsmentioning

confidence: 99%

The role of the ER stress-response protein PERK in rhodopsin retinitis pigmentosa

Athanasiou¹,

Aguilà²,

Bellingham³

et al. 2017

Human Molecular Genetics

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Mutations in rhodopsin, the light-sensitive protein of rod cells, are the most common cause of dominant retinitis pigmentosa (RP), a type of inherited blindness caused by the dysfunction and death of photoreceptor cells. The P23H mutation, the most frequent single cause of RP in the USA, causes rhodopsin misfolding and induction of the unfolded protein response (UPR), an adaptive ER stress response and signalling network that aims to enhance the folding and degradation of misfolded proteins to restore proteostasis. Prolonged UPR activation, and in particular the PERK branch, can reduce protein synthesis and initiate cell death through induction of pro-apoptotic pathways. Here, we investigated the effect of pharmacological PERK inhibition on retinal disease process in the P23H-1 transgenic rat model of retinal degeneration. PERK inhibition with GSK2606414A led to an inhibition of eIF2α phosphorylation, which correlated with reduced ERG function and decreased photoreceptor survival at both high and low doses of PERK inhibitor. Additionally, PERK inhibition increased the incidence of inclusion formation in cultured cells overexpressing P23H rod opsin, and increased rhodopsin aggregation in the P23H-1 rat retina, suggesting enhanced P23H misfolding and aggregation. In contrast, treatment of P23H-1 rats with an inhibitor of eIF2α phosphatase, salubrinal, led to improved photoreceptor survival. Collectively, these data suggest the activation of PERK is part of a protective response to mutant rhodopsin that ultimately limits photoreceptor cell death.

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“…P23H is the most common RP-associated rhodopsin mutation in North America (Dryja et al 1990;Mendes et al 2005), and has been characterized in a number of cell and animal models. P23H rhodopsin consistently displays poor stability (Krebs et al 2010;Chen et al 2014), aggregation in the ER (Chiang et al 2012b), and disrupted transducin activation (Opefi et al 2013;Chen et al 2014), leading to severe retinal degeneration (Cideciyan et al 1998;Athanasiou et al 2017;LaVail et al 2018). The less severe M39R mutation, which is also associated with RP, has been studied using both bovine and human rhodopsin genes displaying a more severe cytosolic aggregation phenotype in the human gene background (Davies et al 2012;Ramon et al 2014).…”

Section: Magnitude Of Light-activated Signal Transduction In Yeast Comentioning

confidence: 99%

Coupling of Human Rhodopsin to a Yeast Signaling Pathway Enables Characterization of Mutations Associated with Retinal Disease

et al. 2018

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G protein-coupled receptors (GPCRs) are crucial sensors of extracellular signals in eukaryotes, with multiple GPCR mutations linked to human diseases. With the growing number of sequenced human genomes, determining the pathogenicity of a mutation is challenging, but can be aided by a direct measurement of GPCR-mediated signaling. This is particularly difficult for the visual pigment rhodopsin-a GPCR activated by light-for which hundreds of mutations have been linked to inherited degenerative retinal diseases such as retinitis pigmentosa. In this study, we successfully engineered, for the first time, activation by human rhodopsin of the yeast mating pathway, resulting in signaling via a fluorescent reporter. We combine this novel assay for rhodopsin lightdependent activation with studies of subcellular localization, and the upregulation of the unfolded protein response in response to misfolded rhodopsin protein. We use these assays to characterize a panel of rhodopsin mutations with known molecular phenotypes, finding that rhodopsin maintains a similar molecular phenotype in yeast, with some interesting differences. Furthermore, we compare our assays in yeast with clinical phenotypes from patients with novel disease-linked mutations. We demonstrate that our engineered yeast strain can be useful in rhodopsin mutant classification, and in helping to determine the molecular mechanisms underlying their pathogenicity. This approach may also be applied to better understand the clinical relevance of other human GPCR mutations, furthering the use of yeast as a tool for investigating molecular mechanisms relevant to human disease.

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

Cited by 39 publications

References 68 publications

Stimulation of AMPK prevents degeneration of photoreceptors and the retinal pigment epithelium

Stimulation of AMPK prevents degeneration of photoreceptors and the retinal pigment epithelium

The role of the ER stress-response protein PERK in rhodopsin retinitis pigmentosa

Coupling of Human Rhodopsin to a Yeast Signaling Pathway Enables Characterization of Mutations Associated with Retinal Disease

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