Pedro M. Domingos Lab

	We use Drosophila as a model system to study the molecular and cellular signaling mechanisms involved in the degeneration of the photoreceptors, the cells that sense light in the visual system.
	Pedro M. Domingos Investigador Principal PhD in Developmental Biology, 2001, University College London Phone (+351) 214469844/45 |  (+351) 211157781 Email domingp@itqb.unl.pt

Research Interests

The endoplasmic reticulum (ER) is the cell organelle where secreted and membrane proteins are synthesized and folded. This process requires the recruitment of ribosomes, translocation of the nascent peptides into the lumen of the ER, and a variety of post-translational modifications and folding events. When the folding capacity of the ER is impaired, the presence of misfolded proteins in the ER causes stress to the cell (“ER stress”) and activates a cellular response, the Unfolded Protein Response (UPR), to restore homeostasis in the ER. The UPR is mediated by several signaling pathways, which sense stress in the ER and activate a variety of cellular responses, such as, translational attenuation, to reduce protein synthesis and prevent further accumulation of unfolded proteins and the transcriptional upregulation of genes encoding ER chaperones and enzymes, to increase the folding capacity of the ER. However, in situations where ER stress is severe or prolonged, or when the cellular responses induced by UPR are not sufficient to overcome the origin of ER stress, cells can undergo programmed cell death (Apoptosis).

Retinitis pigmentosa (RP) is a major cause of human blindness. In this disease, 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 dominant degeneration of the retina and most of these mutations produce misfolded forms of Rhodopsin 1, which are not properly processed and accumulate in the ER.

We have shown that one of the branches of the UPR, the IRE1/Xbp1 signaling pathway has a protective role against ninaE induced photoreceptor degeneration. We are currently using the tools of modern genetics, cell biology and imaging to investigate the genes downstream of the IRE1/Xbp1 signaling pathway that regulate photoreceptor degeneration.  

Group Members

• Pedro Domingos, Lab head

• Fátima Cairrão, Post-Doc Fellow

• Gonçalo Poças, Post-Doc Fellow

• Catarina Gaspar, PhD Student

• Cristiana Santos, PhD Student

• Erika Carvalho, PhD Student

Alumni

• Yolanda Afonso, Masters Student

• Vanya Rasheva, Post-Doc Fellow

• Dina Coelho, PhD Student

• Nadine Schweizer, PhD Student

• João Coelho, Post-Doc Fellow

Selected Publications

1. Gaspar CJ, Gomes T, Martins JC, Melo MN, Adrain C, Cordeiro TN, Domingos PM (2023) Xport-A functions as a chaperone by stabilizing the first five transmembrane domains of rhodopsin-1. iScience Oct 23;26(12):108309. doi: 10.1016/j.isci.2023.108309. PMID: 38025784; PMCID: PMC10663829.

2. Rita Rosado-Ramos*, Gonçalo M Poças*, Daniela Marques, Alexandre Foito, David M Sevillano, Mafalda Lopes-da-Silva, Luís G Gonçalves, Regina Menezes, Marcel Ottens, Derek Stewart, Alain Ibáñez de Opakua, Markus Zweckstetter, Miguel C Seabra, César S Mendes, Tiago Fleming Outeiro, Pedro M Domingos, Cláudia N Santos (2023) Genipin prevents alpha-synuclein aggregation and toxicity by affecting endocytosis, metabolism and lipid storage. Nature Communications (10.1038/s41467-023-37561-2) * these authors contributed equally.

3. Fátima Cairrão,  Cristiana C. Santos, Adrien Le Thomas, Scot Marsters, Avi Ashkenazi & Pedro M. Domingos (2022) Pumilio protects Xbp1 mRNA from regulated Ire1-dependent decay. Nature Communications (https://www.nature.com/articles/s41467-022-29105-x) 

4. Catarina J Gaspar, Lígia C Vieira, Cristiana C Santos, John C Christianson, David Jakubec, Kvido Strisovsky, Colin Adrain, Pedro M Domingos (2022) EMC is required for biogenesis of Xport-A, an essential chaperone of Rhodopsin-1 and the TRP channel. EMBO Reports (https://doi.org/10.15252/embr.202153210) 

5. Domingos PM*, Andreas Jenny, Keon F Combie, David del Alamo, Marek Mlodzik, Hermann Steller, Bertrand Mollereau* (2019) Regulation of Numb during planar cell polarity establishment in the Drosophila eye. Mech Dev. 2019 Dec;160:103583. doi:10.1016/j.mod.2019.103583. (https://www.biorxiv.org/content/10.1101/686840v1) *corresponding authors

6. Branco-Santos J, Herrera F*, Pocas GM, Pires-Afonso Y, Giorgini F, Domingos PM*, Outeiro TF* (2017) Protein Phosphatase 1 Regulates Huntingtin Exon 1 Aggregation And Toxicity. Hum Mol Genet. Oct 1;26(19):3763-3775. doi: 10.1093/hmg/ddx260. (http://biorxiv.org/content/early/2017/05/10/135954) *corresponding authors

7. Poças GM, Branco-Santos J, Herrera F, Outeiro TF, Domingos PM. (2015) α-Synuclein modifies mutant huntingtin aggregation and neurotoxicity in Drosophila. Hum Mol Genet, 24(7): 1898-1907. doi: 10.1093/hmg/ddu606.

8. Dina S. Coelho, Fatima Cairrão, Xiaomei Zeng, Elisabete Pires, Ana V. Coelho, David Ron, Hyung Don Ryoo, Pedro M. Domingos (2013) Xbp1-Independent Ire1 Signaling Is Required for Photoreceptor Differentiation and Rhabdomere Morphogenesis in Drosophila. Cell Reports 5, 791–80.

Laboratory's Website

For further information please visit the laboratory's website (under construction) 

Sinalização Celular em Drosophila (PT)

No nosso laboratório estudamos a degeneração dos fotoreceptores, os neurónios que são sensíveis à luz no sistema visual. Utilizamos a Drosophila melanogaster (mosca do vinagre) como organismo experimental e o nosso objectivo é identificar genes que controlem o processo de degeneração dos fotoreceptores, num modelo biológico para a doença humana Retinite Pigmentosa. Estamos particularmente interessados em genes que regulem a degeneração dos fotoreceptores em casos de Retinite Pigmentosa provocados pela acumulação no retículo endoplásmico de formas incorrectas de Rodopsina, a proteína que detecta a luz nos fotoreceptores. 

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