Neurodegenerative conditions like Alzheimer’s, Parkinson’s and prion disease result from the misfolding and aggregation of key neuronal proteins. In fact, the striking loss of cognitive and motor abilities in these age-related illnesses is frequently linked to the appearance of abnormal protein deposits in neurons. However, the presence of plaques and tangles in elderly brains is not a precondition for neurodegeneration. Rather, neuronal damage is triggered by small precursors of these rogue proteins decades before brain deposits and clinical symptoms become evident.
Our research has two continuing goals:
- understanding the cellular and molecular mechanisms by which misfolded protein oligomers induce early neurotoxicity in vivo
- transforming this information into novel drug screening methodologies to identify anti-neurodegeneration compounds
To pursue these goals, we employ cell biological, biochemical and behavioral approaches in genetically and pharmacologically manipulated zebrafish embryos. These small vertebrates offer key experimental advantages, such as their external development and optical clarity, which allow for high resolution imaging of physiological processes in neurons.
Of special interest to our lab is the involvement of the cellular prion protein (PrPC) as a common receptor for various neurotoxic species in the brain, including amyloid β (aβ), α-synuclein and its own misfolded isoform, PrPSc. This intriguing role of PrPC as a broad transducer of neurotoxicity relies on its physiological ability to elicit complex intracellular signals. Therefore, many of our efforts are aimed at analyzing how PrP modulates molecular pathways and cellular events in health and disease.
The consistent lack of overt phenotypes in mice devoid of PrPC prompted our laboratory to address this question using zebrafish. Upon identifying fish PrPs and analyzing embryonic loss- and gain-of-function phenotypes, we showed that PrPC modulates cell-cell communication, either by promoting cell-contact formation through homophilic interactions, or by controlling the cell surface exposure of adhesion molecules via Src family kinase-dependent (SFK) phosphorylation. The latter mechanism is very relevant to Alzheimer’s neurodegeneration, as it also explains the toxic overactivation of mammalian glutamate receptors triggered by aβ oligomers.
Currently, our projects center around the following topics:
- The complex roles of PrPC- and SFK-associated pathways during early morphogenesis and neural development, their genetic redundancy and compensatory mechanisms, maternal and zygotic gene functions.
- Neurotoxic pathways induced by amyloids in vivo and their connection to the PrPC/SFK-mediated control of neuroreceptor and adhesion molecule activity.
- Spatiotemporal dynamics of amyloid aggregation in the nervous system, their cellular uptake and processing.
- Development of embryo-based neurotoxicity reporter assays to screen for anti-neurodegeneration drugs.
Our laboratory is equipped with state-of-the-art instrumentation, including micromanipulation and microinjection stations for the generation of transgenic and CRISPR-Cas mutant fish, optical sectioning and high resolution fluorescence confocal microscopes, systems for DNA and protein detection and analysis, molecular biology and bioinformatic resources, an automated behavioral tracking device and a dedicated zebrafish facility housing 3000 adult wildtype, mutant and transgenic animals.
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Dr. Edward Málaga-Trillo was born in Lima, Perú, completed his undergraduate studies in Biology at Universidad Peruana Cayetano Heredia (UPCH) and carried out his Ph.D. in Microbiology and Immunology at the University of Miami School of Medicine and the Max-Planck-Institut für Biologie in Tübingen, Germany. After postdoctoral trainings in Evolutionary Genomics and Developmental Neurobiology at the University of Konstanz, Germany, he was appointed Wissenschaftlicher Assistent (Assistant Professor) there and, upon completing the German Habilitation, Privatdozent (Adj. Associate Professor) in Developmental Neurobiology. Throughout his career, he acquired specialized training in fish genetic manipulations (Stirling, Scotland), Molecular Evolution (Hayama, Japan), Evolutionary Genomics (Eugene, USA) and Developmental Genetics of Zebrafish (Woods Hole, USA). His published work focuses on the cellular and molecular basis of neuronal degeneration and regeneration. Dr. Málaga-Trillo’s group pioneered the use of zebrafish as an animal model to study molecular mechanisms of neurodegeneration, reporting in 2009 the first in vivo function of the prion protein. In 2015 he returned as Full Professor to UPCH, where he set up the first Peruvian zebrafish laboratory at the Developmental Neurobiology Research Unit. Since 2018 he is President of the Latin American Zebrafish Network (LAZEN).
- Málaga-Trillo E and K Ochs. 2016. Uncontrolled SFK-mediated protein trafficking in prion and Alzheimer's disease. Prion 10 (5): 352-361.
- 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.
- 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.
- Pinzón-Olejua A, Welte C, Abdesselem H, Málaga-Trillo E and CAO Stuermer. 2014. Essential roles of zebrafish rtn4/Nogo orthologues in embryonic development. Neural Development 9:8.
- Solis GP, Radon Y, Sempou E, Jechow K, Stuermer CAO and Málaga-Trillo E. 2013. Conserved roles of the prion protein domains on subcellular localization and cell-cell adhesion. PLoS ONE, 8(7): e70327.
- 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.
- Málaga-Trillo E and E Sempou. 2009. PrPs: Proteins with a Purpose (Lessons from the zebrafish). Prion, 3(3).
- 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. PLoS Biology7(3):e75.
Latin American Zebrafish Network (LAZEN)
We are members of the Latin American Zebrafish Network LAZEN, founded in 2010 to promote zebrafish research and foster collaborations in the region through courses, meetings and other activities. Since then, the Latin American zebrafish community has steadily grown with member labs in Chile, Uruguay, Argentina, Brazil, México and Perú.
Every two years, a major zebrafish event is held in a different LAZEN country. In 2020, we will be hosting the VI International LAZEN Practical Course and Symposium in Perú. For this tenth anniversary of LAZEN, we are making an extra effort to deliver a world-class event in terms of invited speakers, topics and international visibility. The course is set to take place at UPCH from March 14 to 27 in Lima, and the Symposium from March 29 to April 02 in Cusco, former capital of the Inca Empire. Official announcements will follow. PLEASE SPREAD THE WORD AND SAVE THE DATES!
For more information about LAZEN, please see: