title: Proteomic survey reveals altered energetic patterns and metabolic failure prior to retinal degeneration.
abstract: Inherited mutations that lead to misfolding of the visual pigment rhodopsin (Rho) are a prominent cause of photoreceptor neuron (PN) degeneration and blindness. How Rho proteotoxic stress progressively impairs PN viability remains unknown. To identify the pathways that mediate Rho toxicity in PNs, we performed a comprehensive proteomic profiling of retinas from Drosophila transgenics expressing Rh1(P37H), the equivalent of mammalian Rho(P23H), the most common Rho mutation linked to blindness in humans. Profiling of young Rh1(P37H) retinas revealed a coordinated upregulation of energy-producing pathways and attenuation of energy-consuming pathways involving target of rapamycin (TOR) signaling, which was reversed in older retinas at the onset of PN degeneration. We probed the relevance of these metabolic changes to PN survival by using a combination of pharmacological and genetic approaches. Chronic suppression of TOR signaling, using the inhibitor rapamycin, strongly mitigated PN degeneration, indicating that TOR signaling activation by chronic Rh1(P37H) proteotoxic stress is deleterious for PNs. Genetic inactivation of the endoplasmic reticulum stress-induced JNK/TRAF1 axis as well as the APAF-1/caspase-9 axis, activated by damaged mitochondria, dramatically suppressed Rh1(P37H)-induced PN degeneration, identifying the mitochondria as novel mediators of Rh1(P37H) toxicity. We thus propose that chronic Rh1(P37H) proteotoxic stress distorts the energetic profile of PNs leading to metabolic imbalance, mitochondrial failure, and PN degeneration and therapies normalizing metabolic function might be used to alleviate Rh1(P37H) toxicity in the retina. Our study offers a glimpse into the intricate higher order interactions that underlie PN dysfunction and provides a useful resource for identifying other molecular networks that mediate Rho toxicity in PNs.
authors.affiliation: Research Unit Protein Science, Helmholtz Zentrum München (GmbH)-German Research Center for Environmental Health, D-85764 Neuherberg, Germany, Department of Translational Medicine and Neurogenetics and Department of Development and Stem Cells, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104-INSERM U964-Université de Strasbourg, 67404 Illkirch, France, Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, and Center for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Griciuc
authors.forename: Michel J
authors.initials: MJ
authors.lastname: Roux
authors.forename: Juliane
authors.initials: J
authors.lastname: Merl
authors.forename: Angela
authors.initials: A
authors.lastname: Giangrande
authors.forename: Stefanie M
authors.initials: SM
authors.lastname: Hauck
authors.forename: Liviu
authors.initials: L
authors.lastname: Aron
authors.forename: Marius
authors.initials: M
authors.lastname: Ueffing
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D053453:Caspase 9 / Q000378:metabolism; D004396:Coloring Agents; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster; D004596:Electroretinography; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D060746:Endoplasmic Reticulum-Associated Degradation / Q000502:physiology; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D013058:Mass Spectrometry; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects; D009154:Mutation / Q000235:genetics / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects; D017510:Protein Folding; D011492:Protein Hydrolysates / Q000737:chemistry; D040901:Proteomics; D012162:Retinal Degeneration / Q000235:genetics* / Q000378:metabolism*; D012243:Rhodopsin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D014048:Tolonium Chloride
chemical_list: D004396:Coloring Agents; D029721:Drosophila Proteins; D011492:Protein Hydrolysates; C400550:dark protein, Drosophila; D014048:Tolonium Chloride; D012243:Rhodopsin; D058570:TOR Serine-Threonine Kinases; D053453:Caspase 9
keywords: mTOR; metabolism; mitochondria; proteomics; retinitis pigmentosa; rhodopsin