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The prion protein in health and disease

English title The prion protein in health and disease
Applicant Aguzzi Adriano
Number 160329
Funding scheme Project funding (Div. I-III)
Research institution Institut für Neuropathologie Departement für Pathologie Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Pathophysiology
Start/End 01.06.2015 - 31.05.2018
Approved amount 930'678.00
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Keywords (3)

myelination; cell death; prion protein

Lay Summary (German)

Lead
Prionenkrankheiten - einschliesslich der Creutzfeldt-Jakob-Krankheit - sind tödlich verlaufende neurodegenerative Erkrankungen, welche Menschen und andere Säugetiere befallen können. Weil die grundlegende Biologie der Prionen noch nicht verstanden ist, sind gegenwärtig keine Therapien verfügbar.
Lay summary

Inhalt und Ziele des Forschungsprojekts

In der Vergangenheit haben wir uns darauf konzentriert, die physiologische Rolle des N1-Fragments des Prion-Proteins (PrP) zu klären. Wir haben uns dabei auf eine relativ neue, von uns perfektionierte Technik gestützt (chronische organotypische Kleinhirnkulturen), um die Mechanismen zu studieren, welche mit dem durch Prionen verursachen Zelltod zusammen hängen.

Darauf werden wir nun weiter aufbauen: Wir werden unsere Bestrebungen weiterführen, die Bedeutung des N-Terminus des Prionproteins zu untersuchen, sowohl unter physiologischen Bedingungen wie auch in der Krankheit. Zudem beabsichtigen wir, die Mechanismen zu verstehen, welche zur Spongiose führen, welche als typisches Merkmal bei Prionenerkrankungen auftritt.

Ziel 1: Untersuchung der Rolle des N-Terminus des Prionproteins in der Myelinisierung

Ziel 2: Erforschung der Rolle des N-Terminus in vererbbaren Prionenerkrankungen

Ziel 3: Untersuchung der für die Spongiosis verantwortlichen Mechanismen

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Obschon es sich bei den Prionenerkrankungen um seltene Krankheiten handelt, so entstehen für die Betroffenen und ihre Angehörigen doch immense persönliche und soziale Lasten. Die Mechanismen, welche zu diesen verheerenden Erkrankungen führen, sind  nach wie vor schlecht verstanden. Als Folge davon fehlen Therapiestrategien; die entmutigenden Resultate laufender therapeutischer Versuche unterstreichen den Bedarf nach weitergehenden Bemühungen zum Verständnis der zugrundeliegenden Mechanismen.


 

Direct link to Lay Summary Last update: 28.12.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
Structural characterization of POM6 Fab and mouse prion protein complex identifies key regions for prions conformational conversion
Baral Pravas Kumar, Swayampakula Mridula, Aguzzi Adriano, James Michael N. G. (2018), Structural characterization of POM6 Fab and mouse prion protein complex identifies key regions for prions conformational conversion, in The FEBS Journal, 285(9), 1701-1714.
GPR56/ADGRG1 regulates development and maintenance of peripheral myelin
Ackerman Sarah D., Luo Rong, Poitelon Yannick, Mogha Amit, Harty Breanne L., D’Rozario Mitchell, Sanchez Nicholas E., Lakkaraju Asvin K.K., Gamble Paul, Li Jun, Qu Jun, MacEwan Matthew R., Ray Wilson Zachary, Aguzzi Adriano, Feltri M. Laura, Piao Xianhua, Monk Kelly R. (2018), GPR56/ADGRG1 regulates development and maintenance of peripheral myelin, in The Journal of Experimental Medicine, 215(3), 941-961.
Binding of Polythiophenes to Amyloids: Structural Mapping of the Pharmacophore
Schütz Anne K., Hornemann Simone, Wälti Marielle A., Greuter Ladina, Tiberi Cinzia, Cadalbert Riccardo, Gantner Matthias, Riek Roland, Hammarström Per, Nilsson K. Peter R., Böckmann Anja, Aguzzi Adriano, Meier Beat H. (2018), Binding of Polythiophenes to Amyloids: Structural Mapping of the Pharmacophore, in ACS Chemical Neuroscience, 9(3), 475-481.
Toward Therapy of Human Prion Diseases
Aguzzi Adriano, Lakkaraju Asvin K.K., Frontzek Karl (2018), Toward Therapy of Human Prion Diseases, in Annual Review of Pharmacology and Toxicology, 58(1), 331-351.
The biological function of the cellular prion protein: an update
Wulf Marie-Angela, Senatore Assunta, Aguzzi Adriano (2017), The biological function of the cellular prion protein: an update, in BMC Biology, 15(1), 34-34.
Inhibition of group-I metabotropic glutamate receptors protects against prion toxicity
Goniotaki Despoina, Lakkaraju Asvin K. K., Shrivastava Amulya N., Bakirci Pamela, Sorce Silvia, Senatore Assunta, Marpakwar Rajlakshmi, Hornemann Simone, Gasparini Fabrizio, Triller Antoine, Aguzzi Adriano (2017), Inhibition of group-I metabotropic glutamate receptors protects against prion toxicity, in PLOS Pathogens, 13(11), e1006733-e1006733.
Absolute Quantification of Amyloid Propagons by Digital Microfluidics
Pfammatter Manuela, Andreasen Maria, Meisl Georg, Taylor Christopher G., Adamcik Jozef, Bolisetty Sreenath, Sánchez-Ferrer Antoni, Klenerman David, Dobson Christopher M., Mezzenga Raffaele, Knowles Tuomas P. J., Aguzzi Adriano, Hornemann Simone (2017), Absolute Quantification of Amyloid Propagons by Digital Microfluidics, in Analytical Chemistry, 89(22), 12306-12313.
Microglia in prion diseases
Aguzzi Adriano, Zhu Caihong (2017), Microglia in prion diseases, in Journal of Clinical Investigation, 127(9), 3230-3239.
Modifiers of prion protein biogenesis and recycling identified by a highly parallel endocytosis kinetics assay
Ballmer Boris A., Moos Rita, Liberali Prisca, Pelkmans Lucas, Hornemann Simone, Aguzzi Adriano (2017), Modifiers of prion protein biogenesis and recycling identified by a highly parallel endocytosis kinetics assay, in Journal of Biological Chemistry, 292(20), 8356-8368.
Prion pathogenesis is unaltered in the absence of SIRPα-mediated "don't-eat-me" signaling
Nuvolone Mario, Paolucci Marta, Sorce Silvia, Kana Veronika, Moos Rita, Matozaki Takashi, Aguzzi Adriano (2017), Prion pathogenesis is unaltered in the absence of SIRPα-mediated "don't-eat-me" signaling, in PLOS ONE, 12(5), e0177876-e0177876.
Protease resistance of infectious prions is suppressed by removal of a single atom in the cellular prion protein
Leske Henning, Hornemann Simone, Herrmann Uli Simon, Zhu Caihong, Dametto Paolo, Li Bei, Laferriere Florent, Polymenidou Magdalini, Pelczar Pawel, Reimann Regina Rose, Schwarz Petra, Rushing Elisabeth Jane, Wüthrich Kurt, Aguzzi Adriano (2017), Protease resistance of infectious prions is suppressed by removal of a single atom in the cellular prion protein, in PLOS ONE, 12(2), e0170503-e0170503.
Cystatin F is a biomarker of prion pathogenesis in mice
Nuvolone Mario, Schmid Nicolas, Miele Gino, Sorce Silvia, Moos Rita, Schori Christian, Beerli Roger R., Bauer Monika, Saudan Philippe, Dietmeier Klaus, Lachmann Ingolf, Linnebank Michael, Martin Roland, Kallweit Ulf, Kana Veronika, Rushing Elisabeth J., Budka Herbert, Aguzzi Adriano (2017), Cystatin F is a biomarker of prion pathogenesis in mice, in PLOS ONE, 12(2), e0171923-e0171923.
Neurotoxic Antibodies against the Prion Protein Do Not Trigger Prion Replication
Frontzek Karl, Pfammatter Manuela, Sorce Silvia, Senatore Assunta, Schwarz Petra, Moos Rita, Frauenknecht Katrin, Hornemann Simone, Aguzzi Adriano (2016), Neurotoxic Antibodies against the Prion Protein Do Not Trigger Prion Replication, in PLOS ONE, 11(9), e0163601-e0163601.
The prion protein is an agonistic ligand of the G protein-coupled receptor Adgrg6
Küffer Alexander, Lakkaraju Asvin K. K., Mogha Amit, Petersen Sarah C., Airich Kristina, Doucerain Cédric, Marpakwar Rajlakshmi, Bakirci Pamela, Senatore Assunta, Monnard Arnaud, Schiavi Carmen, Nuvolone Mario, Grosshans Bianka, Hornemann Simone, Bassilana Frederic, Monk Kelly R., Aguzzi Adriano (2016), The prion protein is an agonistic ligand of the G protein-coupled receptor Adgrg6, in Nature, 536(7617), 464-468.
Phase Separation: Linking Cellular Compartmentalization to Disease
Aguzzi Adriano, Altmeyer Matthias (2016), Phase Separation: Linking Cellular Compartmentalization to Disease, in Trends in Cell Biology, 26(7), 547-558.
Homozygous calreticulin mutations in patients with myelofibrosis lead to acquired myeloperoxidase deficiency
Theocharides A. P. A., Lundberg P., Lakkaraju A. K. K., Lysenko V., Myburgh R., Aguzzi A., Skoda R. C., Manz M. G. (2016), Homozygous calreticulin mutations in patients with myelofibrosis lead to acquired myeloperoxidase deficiency, in Blood, 127(25), 3253-3259.
A neuroprotective role for microglia in prion diseases
Zhu Caihong, Herrmann Uli S., Falsig Jeppe, Abakumova Irina, Nuvolone Mario, Schwarz Petra, Frauenknecht Katrin, Rushing Elisabeth J., Aguzzi Adriano (2016), A neuroprotective role for microglia in prion diseases, in The Journal of Experimental Medicine, 213(6), 1047-1059.
Strictly co-isogenic C57BL/6J- Prnp−/− mice: A rigorous resource for prion science
Nuvolone Mario, Hermann Mario, Sorce Silvia, Russo Giancarlo, Tiberi Cinzia, Schwarz Petra, Minikel Eric, Sanoudou Despina, Pelczar Pawel, Aguzzi Adriano (2016), Strictly co-isogenic C57BL/6J- Prnp−/− mice: A rigorous resource for prion science, in The Journal of Experimental Medicine, 213(3), 313-327.
Differential Toxicity of Antibodies to the Prion Protein
Reimann Regina R., Sonati Tiziana, Hornemann Simone, Herrmann Uli S., Arand Michael, Hawke Simon, Aguzzi Adriano (2016), Differential Toxicity of Antibodies to the Prion Protein, in PLOS Pathogens, 12(1), e1005401-e1005401.
Cell Biology of Prions and Prionoids: A Status Report
Aguzzi Adriano, Lakkaraju Asvin K.K. (2016), Cell Biology of Prions and Prionoids: A Status Report, in Trends in Cell Biology, 26(1), 40-51.

Collaboration

Group / person Country
Types of collaboration
Michael James, University of Alberta, Edmonton Canada (North America)
- in-depth/constructive exchanges on approaches, methods or results
Pawel Liberski, Laboratory of Electron Microscopy and Neuropathology, Univ. Lodz Poland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Nat Kav, Department of Agricultural, Food and Nutritional Science, University of Alberta Canada (North America)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Seminar CBG May Planck Institute Individual talk Prions: physiology and toxicity 02.03.2018 Dresden, Germany Aguzzi Adriano;
Centre for Misfolding Diseases Intl. Conference 2018 Talk given at a conference Protein aggregation and pathways of toxicity 27.01.2018 Taormina, Italy Aguzzi Adriano;
, 2nd Duesseldorf-Juelich-Symposium on Neurodegenerative Diseases: “Formation, aggregation and propagation of amyloids” Talk given at a conference The surprising biology of mammalian prions 28.11.2017 Düsseldorf, Germany Aguzzi Adriano;
, 4th SIAIS-ShanghaiTech Bioforum Talk given at a conference Biology of mammalian prions 14.11.2017 Shangai, China Aguzzi Adriano;
Molecular Biology of Aging 2017, Symposium of the German National Academy of Sciences of Leopoldina Talk given at a conference The surprising biology of mammalian prions 12.10.2017 Berlin, Germany Aguzzi Adriano;
Degeneration of Neuronal Circuits Talk given at a conference The surprising neurobiology of the prion protein 04.09.2017 Lausanne, Switzerland Aguzzi Adriano;
International Conference on Systems Biology of Human Disease (SBHD) Talk given at a conference Molecular Biology of Prions 07.07.2017 Heidelberg, Germany Aguzzi Adriano;
Visit at Karolinska Institutet Individual talk The surprising biology of mammalian prions 27.04.2017 Stockholm, Sweden Aguzzi Adriano;
Gladstone Institute of Neurological Disease Special Seminar Individual talk Function and Dysfunction of Mammalian Prions 03.04.2017 San Francisco, United States of America Aguzzi Adriano;
Propagation in Neurodegenerative Diseases Talk given at a conference Function of the cellular prion protein PrPC and prion toxicity 08.08.2016 Dublin, Ireland Aguzzi Adriano;
Prion 2016 Talk given at a conference PrPC function and prion toxicity 10.05.2016 Tokyo, Japan Aguzzi Adriano;
Third N-RENNT Symposium on Neuroinfectiology Talk given at a conference Understanding prions: how far have we gotten? 15.02.2016 Hannover, Germany Aguzzi Adriano;
EMBO/EMBL Mechanisms of Neurodegeneration Symposium 2015 Individual talk The prion protein is an agonistic ligand of a pro-myelinating GPCR 14.06.2015 Heidelberg, Germany Lakkaraju Asvin;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Sanofi-Meeting Talk 22.05.2017 Frankfurt am Main, Germany Aguzzi Adriano;
Novartis Foundation Meeting Talk 13.08.2015 Basel, Switzerland Aguzzi Adriano;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Podiumsdiskussion "Pionierleistungen in der Medizin an der Schnittstelle von Grundlagenwissenschafte German-speaking Switzerland 2017
Talks/events/exhibitions Fortschritte auf dem Gebiet der Protein-Aggregation International 2016

Awards

Title Year
InBev-Baillet Latour Health Prize 2017

Associated projects

Number Title Start Funding scheme
166945 CureALS - Stress granules and proteostasis in motor neurons: towards a mechanistic understanding of ALS 01.04.2016 Joint Programming
179040 The prion protein in health and disease 01.06.2018 Project funding (Div. I-III)
160672 Immunotherapy of familial prion diseases 01.02.2015 ERA-NET
147660 Calcium imaging of cellular and circuit dysfunctions in neurodegeneration 01.08.2013 Sinergia
141193 The prion protein in health and disease 01.06.2012 Project funding (Div. I-III)

Abstract

Prion diseases are fatal neurodegenerative diseases, including Creutzfeldt-Jakob disease, which affect humans and other mammals. Due to the lack of knowledge of basic prion biology, no treatment options are currently available. We have previously focused on clarifying the physiological role of the N1 fragment of the prion protein (PrP) and exploiting a relatively new technique, cultured organotypic cerebellar slices (COCS), to study mechanisms of prion-induced cell death. To build upon this, we will continue to examine the importance of the N-terminus of PrP under physiological conditions, as well as in disease. Furthermore, we aim to understand the mechanism responsible for spongiosis, a hallmark observed in those affected by prion diseases. Aim1: Examine the role of the N-terminus in myelination Aim 2: Study the role of the N-terminus in familial prion diseasesAim 3: Examine the mechanism responsible for spongiosis in prion disease
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