Edward Málaga-Trillo
AFFILIATION: Full Professor at Universidad Peruana Cayetano Heredia, Department of Biology
TEL: +51 319-0000, ext 233246
EMAIL: Edward.Malaga@upch.pe
WEB: in progress
GROUP NAME: The Málaga-Trillo Lab, Zebrafish Developmental Neurobiology
RESEARCH INTEREST IN FEW WORDS: The cellular and molecular basis of neurodegeneration
SHORT SUMMARY OF RESEARCH INTEREST (MAX. 200 WORDS):
Our laboratory is interested in uncovering the mechanistic basis of human neurodegenerative disease at the cellular and molecular levels. We base our work on growing evidence that the early steps of protein misfolding and aggregation modify key signaling events in neurons, thereby altering their physiology and triggering their death. Using a combination of genetic, cellular, biochemical and behavioral methods in zebrafish embryos, we analyze the role of the cellular prion protein as a key transducer of neurotoxic signals initiated by pathogenic protein species like prions and amyloid beta oligomers. As we seek to extend our knowledge of neurodegeneration pathways, our research aims at identifying novel molecular targets and therapeutic compounds to revert and/or prevent Alzheimer’s, prion and other fatal neurological illnesses.
LIST OF UP TO FIVE RELEVANT PUBLICATIONS:
1. Málaga-Trillo E, Solis GP, Schrock Y, Geiss C, Luncz L, Thomanetz V and CAO Stuermer. 2009. Regulation of embryonic cell adhesion by the prion protein. PLoS Biology 7(3): e1000055. Commented in the same issue: Chiesa R and DA Harris. 2009. PLoS Biology7(3):e75.
2. Shypitsyna A, Málaga-Trillo E, Reuter A and CAO Stuermer. 2011. Origin of Nogo-A by domain shuffling in a jawed vertebrate. Molecular Biology and Evolution, 28(4):1363-70.
3. Ochs K and E Málaga-Trillo. 2014 Common themes in PrP signaling: the Src remains the same. Frontiers in Cell and Developmental Biology 2: 63. DOI: 10.3389/fcell.2014.00063.
4. Sempou E, Biasini E, Pinzon-Olejua A, Harris DA, E Malaga-Trillo. 2016. Activation of zebrafish Src family kinases by the prion protein is an amyloid-beta-sensitive signal that prevents the endocytosis and degradation of E-cadherin/beta-catenin complexes in vivo. Mol Neurodegener 11: 18.
5. Málaga-Trillo E and K Ochs. 2016. Uncontrolled SFK-mediated protein trafficking in prion and Alzheimer's disease. Prion 10 (5): 352-361.
GROUP MEMBERS (NAME, POSITION, EMAIL):*
1. Edward Málaga-Trillo, P.I., Edward.Malaga@upch.pe
2. Marjorie Álvarez Mejía, Ph.D. student, marjorie.alvarez.m@upch.pe
3. Katharina Ochs, Master’s student, Katharina.Ochs@uni-konstanz.de
4. Brenda Delfín Barandiarán, graduate student, brenda.delfin@upch.pe
5. Marina Molina, graduate student, gissela.molina.a@upch.pe
6. Pierina Barturén, graduate student, angela.barturen.l@upch.pe
7. Kevin Lévano, graduate student, klevolin@hotmail.com
8. Yerci Reyes, technical assistant, radi.reyes@upch.pe
9. Francisco Quispealaya, technical assistant, francisco.quispealaya.m@upch.pe
10. Anna Friederitz, intern, anna.friederitz@web.de
11. Leon Patrick Sprenger, intern, Leon.Sprenger@campus.lmu.de
12. Till Dorendorf, intern, till.dorendorf@uni-konstanz.de
FISH FACILITIES (TYPE OF FISH SYSTEM/TANKS, CAPACITY, ETC.)*
-1x Zebtec standalone system, six-rows of 1.1, 4 and 8 liter tanks (Tecniplast)
FISH LINES KEPT IN STOCK:*
-Wildtype: WT Kn, TAB5
-Mutant: Golden
-Transgenic: HB9::GFP, Isl1::GFP, NeuroD::GFP, NeuroD::RFP, Olig2::GFP, BACmpo::GFP, Fli1::GFP
OTHER EQUIPMENT RELATED TO ZEBRAFISH RESEARCH*
-1x Artemia hatchery (Tecniplast)
-1x Zebralab behavioral screening system (Viewpoint)
-3x Stemi 508 stereomicroscopes (Zeiss)
-1x Axiozoom V16 fluorescence stereomicroscope (Zeiss)
-1x LSM880 with Airyscan confocal microscope (Zeiss)
-1x manual micromanipulator (Narishige)
-1x CellTram Vario micromanipulator (Eppendorf)
-1x Injectman NI2 robotic micromanipulator (Eppendorf)
-1x Femtojet Express microinjector (Eppendorf)
-1x Picospritzer microinjector (WPI)
-2x vertical needle pullers (Sutter)
-1x 566 L incubator for embryos
-1x 75 L incubator for embryos
-various systems for DNA and protein electrophoresis (Hoefer and Thermo Scientific)
-Western blot equipment (Hoefer and Biorad)
-1x automatic film developer for Western blot applications (JPI Healthcare)
LAB EXPERTISE AND TECHNICAL CAPABILITIES (RELATED TO ZEBRAFISH RESEARCH)*
-Extraction and electrophoresis of nucleic acids and proteins from adult fish and embryos.
-Immunostaining and Western blot from embryos
-Micromanipulation and microinjection of embryos
-Cell transplantations
-Intracerebral microinjections
-Embryo dissection and preparation
-High resolution confocal microscopy, single planes, Z-stacks, time-lapse, etc.
-Behavioral analyses
-General caretaking and reproduction of fish stocks
SUMMARY OF RESEARCH INTEREST (MAX. 2000 WORDS):
Age-related neurological conditions like Alzheimer’s, Parkinson’s, and Creutzfeldt-Jakob Disease have a common pathological landmark: widespread neurodegeneration often associated with protein misfolding and aggregation. Much of my interest in these fatal disorders was sparked by the unique nature of the cellular prion protein (PrPC), a host-encoded polypeptide capable of converting into a pathological isoform -scrapie (PrPSc)- and assembling into prions, infectious particles that transmit neurodegenerative disease. A key question in prion biology concerns the physiological role of PrPC and its contribution to neurotoxicity. Based on in vitro evidence, many potential roles had been proposed for PrPC but their in vivo relevance remained unclear because of the lack of phenotypes in PrP knockout mice. Using zebrafish embryos, we succeeded in obtaining the first PrP loss- and gain-of-function phenotypes, which have allowed us to characterize the role of PrPC as a signal transduction molecule.
The starting point for this work was the cloning and characterization of fish PrP homologues, since only tetrapod PrPs were known at the time. We found that despite their large evolutionary distance, fish and mammalian PrPs share the same protein architecture (Rivera-Milla et al 2003). We subsequently showed that fish possess two PrPs (PrP-1 and PrP-2) present in the adult fish brain, that they are the genomic orthologues of mammalian PrPs, and that their patterns of molecular evolution are consistent with the existence of an ancient and conserved cellular function for all vertebrate PrPs (Rivera-Milla et al 2006). One of our most significant achievements was the finding that PrP regulates cell-cell communication in vivo (Málaga-Trillo et al. 2009). This study was the first one to show that the lack of PrP produces clear phenotypes in a living organism. We found that knocking down PrP-1 expression at blastula and gastrula stages caused lethal embryonic arrest, and that this phenotype could be partially reverted by mouse PrP. These results underscore the functional similarities between fish and mammalian PrPs. Our work also provided a mechanistic explanation for the PrP-1 phenotype at the cellular level, namely, the impairment of morphogenetic cell movements due to the loss of embryonic cell-cell adhesion. We showed that vertebrate PrPs directly mediate cell-cell contact formation and trigger the activation of Src Family Kinases (SFKs), which in turn control the stability of E-cadherin at the plasma membrane, thereby modulating Ca+2-dependent cell-cell adhesion. In light of the identification of PrP as a neuronal receptor for amyloid beta (aβ, Laurén et al. 2009), our finding of SFKs as physiologically relevant partners of PrP provide testable hypotheses concerning the role of PrPC in prion and Alzheimer´s neurotoxicity (Ochs & Málaga-Trillo 2014). We have addressed the exact molecular mechanisms via which PrPC and SFKs regulate embryonic cell adhesion using genetic, biochemical and cell biological approaches in zebrafish (Sempou et al. 2016). Our analyses of PrP gain- and loss-of-function embryos revealed that PrP prevents the endocytosis of E-cadherin adhesion complexes via the Src family kinases (SFKs) Fyn and Yes. Remarkably, we found that the PrP-Fyn/Yes-E-cadherin pathway is activated in zebrafish embryonic cells treated with human aβ oligomers, in line with the current view that aβ oligomers require PrP and Fyn to block NMDA receptor endocytosis and trigger synaptic damage. Based on these data, we proposed that SFK signaling contributes to prion and Alzheimer’s neurodegeneration by controlling the cell surface expression of important neuronal proteins like adhesion molecules and neuroreceptors (Málaga-Trillo & Ochs 2016).