Pedro Manuel Dias Neto Domingos

@itqb.unl.pt

Principal Investigator
ITQB-UNL

Pedro Manuel Dias Neto Domingos


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https://researchid.co/domingp
Positions
July 2015 – present – Principal Investigator, ITQB-UNL, Instituto de Tecnologia Química e Biológica – Universidade Nova de Lisboa, Portugal. Research Group Leader and Head of the Laboratory of Cell Signaling in Drosophila
July 2008 – June 2015 – Assistant Investigator, ITQB-UNL, Instituto de Tecnologia Química e Biológica – Universidade Nova de Lisboa, Portugal. Research Group Leader and Head of the Laboratory of Cell Signaling in Drosophila.
April 2002 – June 2008 - Postdoctoral Associate, The Rockefeller University, New York, USA.
Mentor: Hermann Steller.
Sep. 2001- March 2002 – Postdoctoral Associate, The Rockefeller University, New York, USA.
Mentor: Ali Hemmati-Brivanlou.
Sep. 1997-August 2001 - PhD student, National Institute for Medical Research, Mill Hill, London, UK..
Mentor: Robb Krumlauf.

EDUCATION

University of Lisbon, Portugal Bachelor Honors 1989-1995 Biochemistry
University College London, UK PhD 1997-2001 Developmental Biology
Mentor: Robb Krumlauf
The Rockefeller University, USA Postdoc 2001-2008 Genetics
Mentor: Hermann Steller

RESEARCH, TEACHING, or OTHER INTERESTS

Developmental Biology, Cell Biology, Biochemistry, Genetics and Molecular Biology, Genetics

FUTURE PROJECTS

Structure and dynamics of the Xport-A/Rhodopsin1 interaction at atomic resolution

Rhodopsins are essential for vision and mutations in human rhodopsins that perturb its folding cause autosomal dominant Retinitis Pigmentosa, an incurable disease that leads to blindness. This proposal intends to go beyond the state-of-the-art by gaining access to dynamic structural information on chaperone-client protein interactions in membranes by monitoring dynamic intra- and intermolecular interactions of Xport-A (chaperone) with Rhodopsin-1 (client).


Applications Invited
PhD/MSc students
30

Scopus Publications

Scopus Publications

  • Fbxo42 promotes the degradation of Ataxin-2 granules to trigger terminal Xbp1 signaling
    Cristiana C. Santos, Nadine Schweizer, Fátima Cairrão, Juanma Ramirez, Nerea Osinalde, et al.
    Nature Communications, 2025
  • Xport-A functions as a chaperone by stabilizing the first five transmembrane domains of rhodopsin-1
    Catarina J. Gaspar, Tiago Gomes, Joana C. Martins, Manuel N. Melo, Colin Adrain, et al.
    Iscience, 2023
  • Genipin prevents alpha-synuclein aggregation and toxicity by affecting endocytosis, metabolism and lipid storage
    Rita Rosado-Ramos, Gonçalo M. Poças, Daniela Marques, Alexandre Foito, David M. Sevillano, et al.
    Nature Communications, 2023
    Parkinson’s Disease (PD) is a common neurodegenerative disorder affecting millions of people worldwide for which there are only symptomatic therapies. Small molecules able to target key pathological processes in PD have emerged as interesting options for modifying disease progression. We have previously shown that a (poly)phenol-enriched fraction (PEF) of Corema album L. leaf extract modulates central events in PD pathogenesis, namely α-synuclein (αSyn) toxicity, aggregation and clearance. PEF was now subjected to a bio-guided fractionation with the aim of identifying the critical bioactive compound. We identified genipin, an iridoid, which relieves αSyn toxicity and aggregation. Furthermore, genipin promotes metabolic alterations and modulates lipid storage and endocytosis. Importantly, genipin was able to prevent the motor deficits caused by the overexpression of αSyn in a Drosophila melanogaster model of PD. These findings widens the possibility for the exploitation of genipin for PD therapeutics.
  • Semaphorin 4B is an ADAM17-cleaved adipokine that inhibits adipocyte differentiation and thermogenesis
    Abdulbasit Amin, Marina Badenes, Johanna Tüshaus, Érika de Carvalho, Emma Burbridge, et al.
    Molecular Metabolism, 2023
  • The ADAM17 sheddase complex regulator iTAP/Frmd8 modulates inflammation and tumor growth
    Marina Badenes, Emma Burbridge, Ioanna Oikonomidi, Abdulbasit Amin, Érika de Carvalho, et al.
    Life Science Alliance, 2023
    The metalloprotease ADAM17 is a sheddase of key molecules, including TNF and epidermal growth factor receptor ligands. ADAM17 exists within an assemblage, the “sheddase complex,” containing a rhomboid pseudoprotease (iRhom1 or iRhom2). iRhoms control multiple aspects of ADAM17 biology. The FERM domain–containing protein iTAP/Frmd8 is an iRhom-binding protein that prevents the precocious shunting of ADAM17 and iRhom2 to lysosomes and their consequent degradation. As pathophysiological role(s) of iTAP/Frmd8 have not been addressed, we characterized the impact of iTAP/Frmd8 loss on ADAM17-associated phenotypes in mice. We show that iTAP/Frmd8 KO mice exhibit defects in inflammatory and intestinal epithelial barrier repair functions, but not the collateral defects associated with global ADAM17 loss. Furthermore, we show that iTAP/Frmd8 regulates cancer cell growth in a cell-autonomous manner and by modulating the tumor microenvironment. Our work suggests that pharmacological intervention at the level of iTAP/Frmd8 may be beneficial to target ADAM17 activity in specific compartments during chronic inflammatory diseases or cancer, while avoiding the collateral impact on the vital functions associated with the widespread inhibition of ADAM17.
  • Pumilio protects Xbp1 mRNA from regulated Ire1-dependent decay
    Fátima Cairrão, Cristiana C. Santos, Adrien Le Thomas, Scot Marsters, Avi Ashkenazi, et al.
    Nature Communications, 2022
    The unfolded protein response (UPR) maintains homeostasis of the endoplasmic reticulum (ER). Residing in the ER membrane, the UPR mediator Ire1 deploys its cytoplasmic kinase-endoribonuclease domain to activate the key UPR transcription factor Xbp1 through non-conventional splicing of Xbp1 mRNA. Ire1 also degrades diverse ER-targeted mRNAs through regulated Ire1-dependent decay (RIDD), but how it spares Xbp1 mRNA from this decay is unknown. Here, we identify binding sites for the RNA-binding protein Pumilio in the 3′UTR Drosophila Xbp1. In the developing Drosophila eye, Pumilio binds both the Xbp1unspliced and Xbp1spliced mRNAs, but only Xbp1spliced is stabilized by Pumilio. Furthermore, Pumilio displays Ire1 kinase-dependent phosphorylation during ER stress, which is required for its stabilization of Xbp1spliced. hIRE1 can phosphorylate Pumilio directly, and phosphorylated Pumilio protects Xbp1spliced mRNA against RIDD. Thus, Ire1-mediated phosphorylation enables Pumilio to shield Xbp1spliced from RIDD. These results uncover an unexpected regulatory link between an RNA-binding protein and the UPR.
  • EMC is required for biogenesis of Xport-A, an essential chaperone of Rhodopsin-1 and the TRP channel
    Catarina J Gaspar, Lígia C Vieira, Cristiana C Santos, John C Christianson, David Jakubec, et al.
    EMBO Reports, 2022
    The ER membrane protein complex (EMC) is required for the biogenesis of a subset of tail anchored (TA) and polytopic membrane proteins, including Rhodopsin‐1 (Rh1) and the TRP channel. To understand the physiological implications of EMC‐dependent membrane protein biogenesis, we perform a bioinformatic identification of Drosophila TA proteins. From 254 predicted TA proteins, screening in larval eye discs identified two proteins that require EMC for their biogenesis: fan and Xport‐A. Fan is required for male fertility in Drosophila and we show that EMC is also required for this process. Xport‐A is essential for the biogenesis of both Rh1 and TRP, raising the possibility that disruption of Rh1 and TRP biogenesis in EMC mutants is secondary to the Xport‐A defect. We show that EMC is required for Xport‐A TMD membrane insertion and that EMC‐independent Xport‐A mutants rescue Rh1 and TRP biogenesis in EMC mutants. Finally, our work also reveals a role for Xport‐A in a glycosylation‐dependent triage mechanism during Rh1 biogenesis in the endoplasmic reticulum.
  • Presynaptic accumulation of α-synuclein causes synaptopathy and progressive neurodegeneration in Drosophila
    Jessika C Bridi, Erika Bereczki, Saffron K Smith, Gonçalo M Poças, Benjamin Kottler, et al.
    Brain Communications, 2021
    Alpha-synuclein (α-syn) mislocalization and accumulation in intracellular inclusions is the major pathological hallmark of degenerative synucleinopathies, including Parkinson’s disease, Parkinson’s disease with dementia and dementia with Lewy bodies. Typical symptoms are behavioural abnormalities including motor deficits that mark disease progression, while non-motor symptoms and synaptic deficits are already apparent during the early stages of disease. Synucleinopathies have therefore been considered synaptopathies that exhibit synaptic dysfunction prior to neurodegeneration. However, the mechanisms and events underlying synaptopathy are largely unknown. Here we investigated the cascade of pathological events underlying α-syn accumulation and toxicity in a Drosophila model of synucleinopathy by employing a combination of histological, biochemical, behavioural and electrophysiological assays. Our findings demonstrate that targeted expression of human α-syn leads to its accumulation in presynaptic terminals that caused downregulation of synaptic proteins, cysteine string protein, synapsin, and syntaxin 1A, and a reduction in the number of Bruchpilot puncta, the core component of the presynaptic active zone essential for its structural integrity and function. These α-syn-mediated presynaptic alterations resulted in impaired neuronal function, which triggered behavioural deficits in ageing Drosophila that occurred prior to progressive degeneration of dopaminergic neurons. Comparable alterations in presynaptic active zone protein were found in patient brain samples of dementia with Lewy bodies. Together, these findings demonstrate that presynaptic accumulation of α-syn impairs the active zone and neuronal function, which together cause synaptopathy that results in behavioural deficits and the progressive loss of dopaminergic neurons. This sequence of events resembles the cytological and behavioural phenotypes that characterise the onset and progression of synucleinopathies, suggesting that α-syn-mediated synaptopathy is an initiating cause of age-related neurodegeneration.
  • Genotoxic stress triggers the activation of IRE1α-dependent RNA decay to modulate the DNA damage response
    Estefanie Dufey, José Manuel Bravo-San Pedro, Cristian Eggers, Matías González-Quiroz, Hery Urra, et al.
    Nature Communications, 2020
    The molecular connections between homeostatic systems that maintain both genome integrity and proteostasis are poorly understood. Here we identify the selective activation of the unfolded protein response transducer IRE1α under genotoxic stress to modulate repair programs and sustain cell survival. DNA damage engages IRE1α signaling in the absence of an endoplasmic reticulum (ER) stress signature, leading to the exclusive activation of regulated IRE1α-dependent decay (RIDD) without activating its canonical output mediated by the transcription factor XBP1. IRE1α endoribonuclease activity controls the stability of mRNAs involved in the DNA damage response, impacting DNA repair, cell cycle arrest and apoptosis. The activation of the c-Abl kinase by DNA damage triggers the oligomerization of IRE1α to catalyze RIDD. The protective role of IRE1α under genotoxic stress is conserved in fly and mouse. Altogether, our results uncover an important intersection between the molecular pathways that sustain genome stability and proteostasis.
  • Quantification of macronutrients intake in a thermogenetic neuronal screen using drosophila larvae
    Gonçalo M. Poças, Pedro M. Domingos, Christen K. Mirth
    Journal of Visualized Experiments, 2020
    Foraging and feeding behaviors allow animals to access sources of energy and nutrients essential for their development, health, and fitness. Investigating the neuronal regulation of these behaviors is essential for the understanding of the physiological and molecular mechanisms underlying nutritional homeostasis. The use of genetically tractable animal models such as worms, flies, and fish greatly facilitates these types of studies. In the last decade, the fruit fly Drosophila melanogaster has been used as a powerful animal model by neurobiologists investigating the neuronal control of feeding and foraging behaviors. While undoubtedly valuable, most studies examine adult flies. Here, we describe a protocol that takes advantage of the simpler larval nervous system to investigate neuronal substrates controlling feeding behaviors when larvae are exposed to diets differing in their protein and carbohydrates content. Our methods are based on a quantitative colorimetric no-choice feeding assay, performed in the context of a neuronal thermogenetic-activation screen. As a read-out, the amount of food eaten by larvae over a 1 h interval was used when exposed to one of the three dye-labeled diets that differ in their protein to carbohydrates (P:C) ratios. The efficacy of this protocol is demonstrated in the context of a neurogenetic screen in larval Drosophila, by identifying candidate neuronal populations regulating the amount of food eaten in diets of different macronutrient quality. We were also able to classify and group the genotypes tested into phenotypic classes. Besides a brief review of the currently available methods in the literature, the advantages and limitations of these methods are discussed and, also, some suggestions are provided about how this protocol might be adapted to other specific experiments.
  • Regulation of Numb during planar cell polarity establishment in the Drosophila eye
    Pedro M. Domingos, Andreas Jenny, Keon F. Combie, David del Alamo, Marek Mlodzik, et al.
    Mechanisms of Development, 2019
  • Drosophila p53 integrates the antagonism between autophagy and apoptosis in response to stress
    Marion Robin, Abdul Raouf Issa, Cristiana C. Santos, Francesco Napoletano, Céline Petitgas, et al.
    Autophagy, 2019
  • Meeting Report - proteostasis in Ericeira
    Colin Adrain, Sivan Henis-Korenblit, Pedro M. Domingos
    Journal of Cell Science, 2018
  • highroad Is a Carboxypetidase Induced by Retinoids to Clear Mutant Rhodopsin-1 in Drosophila Retinitis Pigmentosa Models
    Huai-Wei Huang, Brian Brown, Jaehoon Chung, Pedro M. Domingos, Hyung Don Ryoo
    Cell Reports, 2018
  • Phosphorylation of iRhom2 Controls Stimulated Proteolytic Shedding by the Metalloprotease ADAM17/TACE
    Miguel Cavadas, Ioanna Oikonomidi, Catarina J. Gaspar, Emma Burbridge, Marina Badenes, et al.
    Cell Reports, 2017
  • Protein phosphatase 1 regulates huntingtin exon 1 aggregation and toxicity
    Joana Branco-Santos, Federico Herrera, Gonçalo M. Poças, Yolanda Pires-Afonso, Flaviano Giorgini, et al.
    Human Molecular Genetics, 2017
  • Adaptive preconditioning in neurological diseases – therapeutic insights from proteostatic perturbations
    B. Mollereau, N.M. Rzechorzek, B.D. Roussel, M. Sedru, D.M. Van den Brink, et al.
    Brain Research, 2016
  • α-Synuclein modifies mutant huntingtin aggregation and neurotoxicity in Drosophila
    G. M. Pocas, J. Branco-Santos, F. Herrera, T. F. Outeiro, P. M. Domingos
    Human Molecular Genetics, 2014
  • Ire1 mediated mRNA splicing in a C-terminus deletion mutant of drosophila Xbp1
    Dina S. Coelho, Catarina J. Gaspar, Pedro M. Domingos
    Plos One, 2014
  • Physiological roles of regulated Ire1 dependent decay
    Dina S. Coelho, Pedro M. Domingos
    Frontiers in Genetics, 2014
  • Xbp1-Independent Ire1 Signaling Is Required for Photoreceptor Differentiation and Rhabdomere Morphogenesis in Drosophila
    Dina S. Coelho, Fatima Cairrão, Xiaomei Zeng, Elisabete Pires, Ana V. Coelho, et al.
    Cell Reports, 2013
  • Cellular responses to endoplasmic reticulum stress and apoptosis
    Vanya I. Rasheva, Pedro M. Domingos
    Apoptosis, 2009
  • Pathways regulating apoptosis during patterning and development
    Pedro M Domingos, Hermann Steller
    Current Opinion in Genetics and Development, 2007
  • Unfolded protein response in a Drosophila model for retinal degeneration
    Hyung Don Ryoo, Pedro M Domingos, Min-Ji Kang, Hermann Steller
    EMBO Journal, 2007
  • Photoreceptor differentiation in Drosophila: From immature neurons to functional photoreceptors
    Bertrand Mollereau, Pedro M. Domingos
    Developmental Dynamics, 2005
  • Spalt transcription factors are required for R3/R4 specification and establishment of planar cell polarity in the Drosophila eye
    Pedro M. Domingos, Marek Mlodzik, César S. Mendes, Samara Brown, Hermann Steller, et al.
    Development, 2004
  • Regulation of R7 and R8 differentiation by the spalt genes
    Pedro M. Domingos, Samara Brown, Rosa Barrio, Kajan Ratnakumar, Benjamin J. Frankfort, et al.
    Developmental Biology, 2004
  • Wise, a context-dependent activator and inhibitor of Wnt signalling
    Nobue Itasaki, C. Michael Jones, Sara Mercurio, Alison Rowe, Pedro M. Domingos, et al.
    Development, 2003
  • Cloning and developmental expression of Baf57 in Xenopus laevis
    Pedro M Domingos, Tetyana V Obukhanych, Curtis R Altmann, A Hemmati-Brivanlou
    Mechanisms of Development, 2002
  • The Wnt/β-catenin pathway posteriorizes neural tissue in Xenopus by an indirect mechanism requiring FGF signalling
    Pedro M. Domingos, Nobue Itasaki, C.Michael Jones, Sara Mercurio, Michael G. Sargent, et al.
    Developmental Biology, 2001