PT  - JOURNAL ARTICLE
AU  - Ana Griciuc
AU  - Michel J. Roux
AU  - Juliane Merl
AU  - Angela Giangrande
AU  - Stefanie M. Hauck
AU  - Liviu Aron
AU  - Marius Ueffing
TI  - Proteomic Survey Reveals Altered Energetic Patterns and Metabolic Failure Prior to Retinal Degeneration
AID  - 10.1523/JNEUROSCI.2982-13.2014
DP  - 2014 Feb 19
TA  - The Journal of Neuroscience
PG  - 2797--2812
VI  - 34
IP  - 8
4099  - http://www.jneurosci.org/content/34/8/2797.short
4100  - http://www.jneurosci.org/content/34/8/2797.full
SO  - J. Neurosci.2014 Feb 19; 34
AB  - 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 Rh1P37H, the equivalent of mammalian RhoP23H, the most common Rho mutation linked to blindness in humans. Profiling of young Rh1P37H 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 Rh1P37H 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 Rh1P37H-induced PN degeneration, identifying the mitochondria as novel mediators of Rh1P37H toxicity. We thus propose that chronic Rh1P37H 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 Rh1P37H 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.