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Griciuc, A. ; Roux, M.J.* ; Merl, J. ; Giangrande, A.* ; Hauck, S.M. ; Aron, L.* ; Ueffing, M.

Proteomic survey reveals altered energetic patterns and metabolic failure prior to retinal degeneration.

J. Neurosci. 34, 2797-2812 (2014)
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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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Mtor ; Metabolism ; Mitochondria ; Proteomics ; Retinitis Pigmentosa ; Rhodopsin; Unfolded Protein Response; Quantitative Mass-spectrometry; Endoplasmic-reticulum Stress; Retinitis-pigmentosa; Cell-death; Er Stress; Drosophila-melanogaster; Rhodopsin Maturation; Signaling Pathways; Growth-control
Sprache englisch
Veröffentlichungsjahr 2014
HGF-Berichtsjahr 2014
ISSN (print) / ISBN 0270-6474
e-ISSN 1529-2401
Zeitschrift Journal of Neuroscience
Quellenangaben Band: 34, Heft: 8, Seiten: 2797-2812 Artikelnummer: , Supplement: ,
Verlag Society for Neuroscience
Verlagsort Washington
Begutachtungsstatus Peer reviewed
Institut(e) CF Metabolomics & Proteomics (CF-MPC)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-505700-001
PubMed ID 24553922
DOI 10.1523/JNEUROSCI.2982-13.2014
WOS ID WOS:000331998200005
Scopus ID 84894046055
Erfassungsdatum 2014-02-22
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