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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.
Pubmed ID: 28065882 RIS Download
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Supplier of fully penetrant rat models of the retinitis pigmentosa type of inherited retinal degeneration, including the following models: * Mutant rhodopsin transgenic rats ** P23H mutant rhodopsin transgenic rats -Three lines with different rates of photoreceptor degeneration ** S334ter mutant rhodopsin transgenic rats -Five lines with different rates of photoreceptor degeneration * RCS (Royal College of Surgeons) rats with inherited retinal dystrophy ** RCS pink-eyed inbred strain ** RCS pigmented congenic strain with slowed rate of retinal dystrophy ** RCS congenic control strains of both pigmentation types, wild-type at the retinal dystrophy (Mertk) genetic locus The resource has been supported by the National Eye Institute (NEI) for the past 19 years to produce and distribute breeding pairs of these animal models to vision scientists. Thus, the following apply: * Request for rats requires only a 1-page letter/e-mail addressing 4 questions * No charge for the animals or tissues (except for shipping costs) * No Material Transfer Agreement (MTA) required * No collaboration requirement (in most cases) The resource usually provides multiple breeding pairs of the rats to vision scientists to generate breeding stock. It can also provide extra animals to breed for immediate experimental work, animals of specific ages (depending upon availability), animals with prior exposure to different lighting conditions, eyes taken at specific ages instead of rats for pilot studies and other experiments (fresh, frozen, dissected in specific ways, or fixed with special fixatives or by different methods), or other tissues (e.g., liver, spleen, brain, testis, etc.) prepared different ways.
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