title: Pharmacological Modulation of Photoreceptor Outer Segment Degradation in a Human iPS Cell Model of Inherited Macular Degeneration.
abstract: Degradation of photoreceptor outer segments (POS) by retinal pigment epithelium (RPE) is essential for vision, and studies have implicated altered POS processing in the pathogenesis of some retinal degenerative diseases. Consistent with this concept, a recently established hiPSC-RPE model of inherited macular degeneration, Best disease (BD), displayed reduced rates of POS breakdown. Herein we utilized this model to determine (i) if disturbances in protein degradation pathways are associated with delayed POS digestion and (ii) whether such defect(s) can be pharmacologically targeted. We found that BD hiPSC-RPE cultures possessed increased protein oxidation, decreased free-ubiquitin levels, and altered rates of exosome secretion, consistent with altered POS processing. Application of valproic acid (VPA) with or without rapamycin increased rates of POS degradation in our model, whereas application of bafilomycin-A1 decreased such rates. Importantly, the negative effect of bafilomycin-A1 could be fully reversed by VPA. The utility of hiPSC-RPE for VPA testing was further evident following examination of its efficacy and metabolism in a complementary canine disease model. Our findings suggest that disturbances in protein degradation pathways contribute to the POS processing defect observed in BD hiPSC-RPE, which can be manipulated pharmacologically. These results have therapeutic implications for BD and perhaps other maculopathies.
authors: Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA; McPherson Eye Research Institute, University of Wisconsin, Madison, Wisconsin, USA.
authors: Ruchira
authors: R
authors: Singh
authors: Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors: David
authors: D
authors: Kuai
authors: Department of Clinical Studies-Philadelphia, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Karina E
authors: KE
authors: Guziewicz
authors: Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors: Jackelyn
authors: J
authors: Meyer
authors: Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors: Molly
authors: M
authors: Wilson
authors: Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors: Jianfeng
authors: J
authors: Lu
authors: Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors: Molly
authors: M
authors: Smith
authors: Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors: Eric
authors: E
authors: Clark
authors: Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors: Amelia
authors: A
authors: Verhoeven
authors: Department of Clinical Studies-Philadelphia, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Gustavo D
authors: GD
authors: Aguirre
authors: Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA; McPherson Eye Research Institute, University of Wisconsin, Madison, Wisconsin, USA; Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, USA. Electronic address: dgamm@wisc.edu.
authors: David M
authors: DM
authors: Gamm
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004285:Dogs; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D018942:Macrolides / Q000494:pharmacology; D008954:Models, Biological; D010084:Oxidation-Reduction; D061251:Primary Cell Culture; D059748:Proteolysis / Q000187:drug effects*; D055214:Retinal Photoreceptor Cell Outer Segment / Q000378:metabolism*; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism*; D020123:Sirolimus / Q000627:therapeutic use*; D014635:Valproic Acid / Q000627:therapeutic use*; D057826:Vitelliform Macular Dystrophy / Q000188:drug therapy*
chemical_list: D004791:Enzyme Inhibitors; D018942:Macrolides; D014635:Valproic Acid; C040929:bafilomycin A1; D020123:Sirolimus