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ER Stress and Photoreceptor Degeneration in Drosophila

Final Report Summary - DROSOERSTRESS (ER Stress and Photoreceptor Degeneration in Drosophila)

The endoplasmic reticulum (ER) is the cell organelle where secretory and membrane proteins are synthesized and folded. When the protein folding capacity of the ER is impaired, the presence of unfolded/misfolded proteins in the ER causes stress on the cell - ER stress - and activates a cellular response, the Unfolded Protein Response (UPR), to restore homeostasis in the ER. The presence of misfolded proteins in the ER and the activation of the UPR have been associated with various human diseases, including neurodegenerative diseases and cancer. Retinitis Pigmentosa (RP) is a major cause of human blindness, in which the photoreceptor cells in the eye progressively degenerate over time. About 30% of autosomal dominant RP cases are caused by mutations in Rhodopsin, the light sensitive protein of photoreceptors. In Drosophila, equivalent mutations in ninaE, the gene encoding Rhodopsin 1, also cause progressive degeneration of the photoreceptors. In many of these ninaE mutations, the respective Rhodopsin 1 proteins are not properly folded and processed in the ER, where they accumulate as misfolded proteins. One of the signaling pathways that mediate the UPR, the IRE1/Xbp1 pathway, is activated by misfolded Rhodopsin1 encoded by the ninaE mutations causing photoreceptor degeneration. A loss-of-function mutation in Xbp1 accelerated the course of retinal degeneration in ninaE mutants, demonstrating that IRE1/Xbp1 signaling has a protective role against ninaE induced photoreceptor degeneration .
It is still not clear, however, how misfolded Rhodopsin 1 (and ER stress) trigger retinal degeneration and which are the IRE1/Xbp1 target genes that mediate this protective effect against photoreceptor degeneration.
Furthermore, important questions need clarification in relation to the role of the UPR in developmental processes and disease. In our research, we addressed these important questions with three specific aims:

Aim 1 – Analysis of the molecular mechanisms required for induction of cell death in the context of ER stress.
Aim 2 – The mechanism of induction of cell protection vs death by Xbp1spliced.
Aim 3 – The developmental role of the UPR during photoreceptor differentiation.

We successfully reached our main goals as initially planned. The results obtained were published (in part) in the paper entitled “Xbp1-Independent Ire1 Signaling Is Required for Photoreceptor Differentiation and Rhabdomere Morphogenesis in Drosophila” by Coelho et al (2013) Cell Reports, 5, 791-801. Other results obtained are still to be published. These results will likely have strong relevance in terms of human health, as ER stress and the activation of the UPR have been described as being important factors not only in Retinitis Pigmentosa but also in other neurodegenerative disorders.