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J Neurosci. 2014 Feb 19;34(8):2797-812. doi: 10.1523/JNEUROSCI.2982-13.2014.

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

Author information

1
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.

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.

KEYWORDS:

mTOR; metabolism; mitochondria; proteomics; retinitis pigmentosa; rhodopsin

PMID:
24553922
DOI:
10.1523/JNEUROSCI.2982-13.2014
[Indexed for MEDLINE]
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