title: Rescue of mutant rhodopsin traffic by metformin-induced AMPK activation accelerates photoreceptor degeneration.
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.
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London, UK.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Athanasiou
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London, UK.
authors.forename: Monica
authors.initials: M
authors.lastname: Aguila
authors.affiliation: School of Biological Sciences, University of Essex, Wivenhoe Park, Essex, UK.
authors.forename: Chikwado A
authors.initials: CA
authors.lastname: Opefi
authors.affiliation: School of Biological Sciences, University of Essex, Wivenhoe Park, Essex, UK.
authors.forename: Kieron
authors.initials: K
authors.lastname: South
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London, UK.
authors.forename: James
authors.initials: J
authors.lastname: Bellingham
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London, UK.
authors.forename: Dalila
authors.initials: D
authors.lastname: Bevilacqua
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London, UK.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Munro
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London, UK.
authors.forename: Naheed
authors.initials: N
authors.lastname: Kanuga
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London, UK.
authors.forename: Francesca E
authors.initials: FE
authors.lastname: Mackenzie
authors.affiliation: Moorfields Eye Hospital NHS Trust, 162 City Road, London, UK.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Dubis
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London, UK.
authors.forename: Anastasios
authors.initials: A
authors.lastname: Georgiadis
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London, UK.
authors.forename: Anna B
authors.initials: AB
authors.lastname: Graca
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London, UK.
authors.forename: Rachael A
authors.initials: RA
authors.lastname: Pearson
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London, UK.
authors.forename: Robin R
authors.initials: RR
authors.lastname: Ali
authors.affiliation: Department of Pharmacology, and Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, USA.
authors.forename: Sanae
authors.initials: S
authors.lastname: Sakami
authors.affiliation: Department of Pharmacology, and Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, USA.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
authors.affiliation: Department of Biochemistry, Boston University Medical School, Boston, Massachusetts, MA, USA.
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Sherman
authors.affiliation: School of Biological Sciences, University of Essex, Wivenhoe Park, Essex, UK.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Reeves
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London, UK.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cheetham
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D008687:Metformin / Q000008:administration & dosage*; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics; D010786:Photoreceptor Cells / Q000187:drug effects / Q000473:pathology; D017510:Protein Folding / Q000187:drug effects; D057165:Proteostasis Deficiencies / Q000235:genetics / Q000473:pathology; D051381:Rats; D012162:Retinal Degeneration / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D012243:Rhodopsin / Q000737:chemistry / Q000235:genetics*; D012374:Rod Cell Outer Segment / Q000187:drug effects / Q000473:pathology; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D050505:Mutant Proteins; D012243:Rhodopsin; D008687:Metformin; D055372:AMP-Activated Protein Kinases