
E. Wanker Lab
Proteomics and Molecular Mechanisms of Neurodegenerative Diseases
Profile
Please check out our lab's project:
"How do proteins that interact with mutated huntingtin affect its abundance? A study of Huntington’s disease in cell models and neurons of Drosophila melanogaster"
Huntington’s disease (HD) is a fatal neurodegenerative disease with progressive loss of motor, cognitive and language abilities, leading to premature death after years of severe suffering. As a neurodegenerative protein misfolding disease, HD is related to Alzheimer’s and Parkinson’s disease, as a rare polyglutamine disease to Kennedy’s disease and the spinocerebellar ataxias.
Misfolding and aggregation of the mutant huntingtin protein with an elongated polyglutamine stretch is at the root of the disease.
We have established HD fly models that enable the investigation of huntingtin proteins, their aggregation and seeding specifically in neurons, in vivo. See: Anne Ast et al. “mHTT Seeding Activity: A Marker of Disease Progression and Neurotoxicity in Models of Huntington's Disease”. Molecular Cell. 2018 Sep 6;71(5):675-688.e6. https://doi.org/10.1016/j.molcel.2018.07.032.*
Also, we have developed technologies that enable the quantitative detection of protein-protein interactions (PPIs) in mammalian cells, like our recent LuTHY assay. See: Trepte et al. “LuTHy: A Double-Readout Bioluminescence-Based Two-Hybrid Technology for Quantitative Mapping of Protein-Protein Interactions in Mammalian Cells.” Molecular Systems Biology. 2018 Jul 11;14(7):e8071. https://doi.org/10.15252/msb.20178071.*
In high-throughput screenings using these technologies, we have recently identified various proteins that interact with wild-type and mutant huntingtin in cell models. Among them, ubiquitin protein ligases (UBLs) and deubiquitinating enzymes (DUBs) are of particular interest to us, because they are known to regulate the degradation of other proteins in mammalian cells.
We are now looking for a PhD candidate to join our team to help elucidate the molecular mechanisms that control wild-type and mutant huntingtin protein levels. Specifically, the project will investigate the influence of E3 ligases and DUBs on the abundance of
wild-type and mutant huntingtin in cell models and in HD transgenic flies.
Using the CRISPR/Cas9 technology on mammalian cells, we will generate cell lines that endogenously express huntingtin fusions, which are tagged with nanoluciferase or fluorescent proteins such mCitrine or mNeonGreen. These cell lines will be used to determine the huntingtin dynamics but also to validate huntingtin-interacting UBL and DUB proteins.
Moreover, through knockdown and overexpression of selected ubiquitin and DUB proteins, e.g., the E3 ligase UBR5, we will assess whether the degradation of mutant huntingtin can be promoted. To this end, we want to determine whether the ubiquitin proteasome system (UPS) or autophagy are predominantly responsible for mutant huntingtin degradation in cells. Furthermore, HD transgenic flies will be used to investigate whether huntingtin degradation in non-dividing post-mitotic neurons is different from fast-dividing non-neuronal cells. Altogether, this work will bring significant contributions to finding a new huntingtin lowering strategy, which is one of the most promising current approaches in the search of treatments for Huntington’s disease.
Become a member of a highly motivated, fun and collaborative team full of ideas. As part of our team you will learn, use and develop a set of sophisticated biochemical, biophysical, cellular, genetic, proteomic, imaging and fly techniques to make a significant contribution towards the elucidation and future therapy of Huntington’s disease.
Our group has been active in protein misfolding disorders and interactomics for many years and has made several pioneering discoveries: The identification of protein aggregation in Huntington’s disease (Scherzinger et al. Cell, 1997), the generation of the first genome-wide protein-protein interaction network (Stelzl et al. Cell, 2005) or the effect of small molecules on misfolded protein species relevant to disease (Ehrnhoefer et al. Nature Structural and Molecular Biology, 2006; Bieschke et al.
Nature Chemical Biology, 2011).
* For a more general review of the significance of Ast et al., see:
https://www.mdc-berlin.de/news/press/predicting-onset-and-course-huntingtons-disease
* For commentary on Trepte et al., see:
https://www.embopress.org/doi/full/10.15252/msb.20188485
https://www.mdc-berlin.de/news/news/two-experiments-one-fell-swoop
Looking forward to meeting enthusiastic candidates!
About our research:
Millions of people worldwide suffer from neurodegenerative disorders, like Alzheimer’s, Parkinson’s or Huntington’s disease. Most of these illnesses break out later in life. Correlated to the current demographic shift towards aging societies in many countries, the number of people affected with neurodegenerative diseases is growing.
Still, we do not understand exactly how neurodegenerative diseases develop. One of the characteristic features many neurodegenerative diseases share is the deposition of abnormally folded proteins in patient brains.
My group's research focusses on ‘Neuroproteomics’, the protein-based investigation of neurodegenerative diseases. We aim to elucidate the molecular principles by which proteins, sometimes abnormally folded, alone or in interaction, lead to cellular toxicity and neuronal dysfunction, causing neurodegeneration.
We pursue two main lines of investigation: Hypothesis-driven molecular studies of protein misfolding, aggregation and spreading, on the one hand, unbiased protein-protein interaction or ‘interactomics’ studies on the other. Click "Research" above to read about our current projects and fields of interest.
Team
Erich Wanker, PhD, DI
Principal Investigator
+49/30/9406-2157
ewanker@mdc-berlin.de
Anne Ast, PhD
Postdoc
+49/30/9406-2636
anne.ast@mdc-berlin.de
Irem Bayraktaroglu, BSc
Master's student
+49/30/9406-3481
irem.bayraktaroglu@mdc-berlin.de
Stephanie Beetz, MSc
Technician
+49/30/9406-2353
stephanie.beetz@mdc-berlin.de
Annett Böddrich, PhD
Senior scientist, project manager
+49/30/9406-2357
a.boeddrich@mdc-berlin.de
Megan Bonsor, MSc
Graduate student
+49/30/9406-3421
megan.bonsor@mdc-berlin.de
Lydia Brusendorf, DI
Technician
+49/30/9406-2636
lydia.brusendorf@mdc-berlin.de
Annika Deckert, PhD
Postdoc, Alzheimer's Association Research Fellow
+49/30/9489-2147
annika.deckert@mdc-berlin.de
Marta Dominguez Martinez, MSc
Graduate student
+49/30/9489-2147
marta.dominguez@mdc-berlin.de
Jana Erlmoser
Undergraduate student
+49/30/9406-2805
jana.erlmoser@mdc-berlin.de
Sabrina Golusik, BTA
Technician
+49/30/9406-2805
sabrina.golusik@mdc-berlin.de
Christian Hänig, DI
Computational scientist, IT, automation
+49/30/9406-2437
c.haenig@mdc-berlin.de
Sarina Hilke
Technician
+49/30/9406-3481
sarina.hilke@mdc-berlin.de
Simona Kostova, MSc
Graduate student
+49/30/9406-2433
simona.kostova@mdc-berlin.de
Mara Liebich
Technician
+49/30/9406-2433
mara.liebich@mdc-berlin.de
Adrian Marti Pastor
Undergraduate student
+49/30/9406-3481
adrian.martipastor@mdc-berlin.de
Nancy Neuendorf, BTA
Senior technician
+49/30/9406-2805
nancy.neuendorf@mdc-berlin.de
Eduardo Silva Ramos, PhD
Postdoc
+49/30/9489-2138
eduardo.ramos@mdc-berlin.de
Sigrid Schnögl, MPhil, MBA
Coordinator
+49/30/9406-2357
sigrid.schnoegl@mdc-berlin.de
Christopher Secker, Dr. med.
Postdoc
+49/30/9406-2433
christopher.secker@mdc-berlin.de
Martina Zenkner, DI
Senior technician, lab manager
+49/30/9406-2357
zenkner@mdc-berlin.de
> Previous members <
Claudia Abraham
Mohammed Ahmed
Anna-Clara Amler
Kathrin Andrich, PhD
Iris Apostel-Krause
Anup Arumughan, PhD
Vinayagam Arunachalam, PhD
Jennifer Doreen Augsten
Katrin Bagola
Bianca Bauer
Lynn van der Beek
Simon Berberich
Annaporna Bhat
Jan Bieschke, PhD
Malla Bimalla
Nicole Bock
Svenja Bolz
Anne Borowski
Lamia Bouguerne
Nisrin Nora Boukantar
Yacine Bounab, PhD
Anja Briese
Raul Bukowiecki
Alexander Buntru, PhD
Anne Busch, PhD
Branca Cajavec
Morena Cauglia
Irene Carod
Laura Benitez Casanova
Gautam Chaurasia, PhD
Ummi Hadiba Ciptasari
Louica Delius
Monishita Dey
Ina Dieckmann
Nea Dierolf
Lisa Diez, PhD
Franziska Dinter
Christin Donner
Ulrike Drewes
Anja Dröge, PhD
Juliane Edel, Master
Dagmar Ehrnhöfer, PhD
Thomas Ehrnhöfer
Sabine Engemann, PhD
Figen Ertas
Claudia Eulenberg
Maik Faltysek
Claudia Felsch
Christian Fink, PhD
Carina Fischer, MSc
Leonhard Fister
Alexandra-Iona Forrai
Raphaele Foulle
Ralf Friedrich, PhD
Clemens Franke
Anja Fritzsche
Joris Geigenmüller, BSc
Klaus Genser, PhD
Heike Göhler, PhD
Gerlinde Grelle
Saskia Gressel
Nicole Groenke
Mirjam Groh
Anja Guhra
Stephanie Haase
Ulrike Hagen
Anne Hahmann
Tobias Hahn, MSc
Mohamed Haji, MSc
Lilli Hammermüller
Anna Happe-Kramer
Renate Hasenbank
Regine Hasenkopf
Antje Haug
Denise Heidler
Michael Henriksen
Markus Hensel, BTA
Martin Herbst, PhD
Christin Hesse
Sheila Hoffmann
Sabine Horn
Inna Hoyer
Ulrike Hübner
Melanie Humpenöder
Ismail Ishola, PhD
Manuela Jacob
Philipp Jäger, PhD
Marina Jahns
Isabelle Jansen
Sha Jin, PhD
Carmen Judis
Ronny Kalis
Sedef Karayel
Stefanie Kasper
Tina Kausel
Irem Kaymak, Trainee
Birgit Kersten, PhD
Christopher Kessler
Daria Kiesel
Sylvia Kietzmann
Loni Klaus
Daniela Kleckers
Konrad Klockmeier, MSc
Maria Knoblich
Young-In Ko, PhD
Matthias Könn, PhD
Susanne Köppen
Marja Kornhuber
Susanne Kostka
Manuel Krispin
Jeffrey Kroetsch, PhD
Sabrina Kruse
Christin Kuschke
Evangelos Kyriazidis, Trainee
Maciej Lalowski, PhD
Hans Lehrach jr.
Iva Lelios
Megan Leong
Anna Lewandowski
Rahel Lewin
Elena Lucas
Barbara Lucke
Marie Lütke-Eversloh
Melanie Manzke
Phoebe Markovic, PhD
Stefan Maul
Sonia Mazzitelli
Benjamin McMahon
Sascha Mintzlaff
Angeli Möller, PhD
Annekathrin Möller, PhD
Katja Mühlenberg, PhD
Eva-Christina Müller, PhD
Stanley Myers O’Mulloy
Sandra Neuendorf
Cecilia Nicoletti
Hannah Niederlechner, MSc
Julia Niepelt
Anna Norton
Yetunde Odunsi
Leon Olivier
Albrecht Otto, PhD
Inken Padberg
Mary Paniscus, MSc
Christine Petersen, PhD
Spyros Petrakis, PhD
Vanessa Pfiffer
Maria Lucia Pigazzini
Erika Pisch
Stephanie Plassmann, PhD
Pablo Porras Millan, PhD
Anita Pras
Ellen Ramminger, PhD
Tamas Rasko, PhD
Kirstin Rau
Susanne Rautenberg
Alexandra Redel
Sean-Patrick Riechers, PhD
Uli Rockenbauch
Susanne Rohn
Eugenia Rojas
Maxi Rothbart
Dana Rotte
Jenny Russ, PhD
Natalja Rutz
Linda Salzwedel
Maria Saßning
Kati Scharf
Franziska Schiele
Franziska Schindler, PhD
Philipp Schleumann
Sebastian Schmid
Michael Schmidt, PhD
Vera Schmiedel
Stefanie Schneider
Anke Schönherr
Eileen Schormann
Nadja Schräpel
Herwig Schüler, PhD
Margitta Schümann
Paul Schultze-Motel, PhD
Aline Schulz, PhD
Sabrina Schulz
Erik Schweitzer, PhD
Derya Sen
Leticia Serra
Maliha Shah, PhD
Luke Southan
Silke Spading
Selma Staege
Uli Stelzl, PhD
Kerstin Stemmer
Kathrin Stilz
Nadine Strempel, PhD
Sarah Stricker, MD
Martin Strödicke, PhD
Jaana Suopanki-Lalowski, PhD
Bernhard Suter, PhD
Babila Tachu, PhD
Anne Tempelmeier
Pallavi Thaore
Lasse Thiem
Anke Thieme
Jan Timm
Engin Toksoez
Philipp Trepte, PhD
Sofie Trummer
Julia Ucar
Patrick Umbach, PhD
Jose Miguel Urquiza
Tobias Vöpel, PhD
Stephanie Wälter, PhD
Anne Wagner, PhD
Lia Walcher
Jacqueline Walter
Katja Welsch, PhD
Ina Wendland, undergraduate student
Carsta Werner
Franziska Wiedemann
Thomas Wiglenda, PhD
Lindsay Willmore
Sascha Wiswedel
Heike Wobst
Uwe Worm
Sargon Yigit
Oleksandr Zabiegalov
Joshua Zelwis
Jana Zielinski
Research
Jan 26, 2021: PhD recruitment round for spring 2021: We are participating. Please check out our lab's project:
How do proteins that interact with mutated huntingtin affect its abundance? A study of Huntington’s disease in cell models and neurons of Drosophila melanogaster
Looking forward to meeting enthusiastic candidates!
My group's research focusses on ‘Neuroproteomics’, the protein-based investigation of neurodegenerative diseases. In detailed, hypothesis-driven studies we address mechanisms of protein misfolding and aggregation, with the aim of understanding the molecular mechanisms of neurodegeneration in Huntington’s, Alzheimer’s and further diseases causally related to the misfolding of proteins. In particular, we aim to elucidate the molecular principles by which abnormally folded proteins, their complexes and aggregates cause cellular toxicity and neuronal dysfunction. In our efforts to promote translation of basic research into benefits for patients, we identify and characterize modulators of protein misfolding cascades in disease (Ehrnhoefer et al., Nat Struct Mol Biol, 2008; Bieschke et al., Nat Chem Biol, 2011). We have previously demonstrated that expanded polyglutamine (polyQ) sequences trigger misfolding and aggregation of N-terminal huntingtin fragments in vitro and in vivo (Scherzinger et al., Cell, 1997; Davis et al., Cell, 1997). More recently, we have started new lines of translational research establishing methods to detect disease-relevant misfolded protein species in biosamples from models and patients. These investigations are directed at the development of predictive disease markers which are a prerequisite for the clinical investigation of new disease-modifying therapies targeting neurodegeneration before symptoms of irreversible neuronal damage arise. In collaboration with Alessandro Prigione, a Delbrück Fellow I have been mentoring since 2013, we have established stem cell research strategies for the rare neurological Leigh syndrome and Huntington’s disease (Lorenz et al. Cell Stem Cell, 2017).
Our second field of activity is systems biology, in particular using interactomics approaches, which are also mainly applied to neurodegenerative disease processes. Previously, we developed an automated yeast two-hybrid (Y2H) system, which we used to generate a focused protein-protein interaction network for the huntingtin protein relevant to Huntington's disease (Goehler et al., Mol. Cell, 2004), as well as a large interaction map of the human proteome (Stelzl et al., Cell, 2005). Recently, we identified highly relevant interactions between the triple A ATPase VCP/p97 and an adaptor protein that effects a fundamental structural change in VCP from a homohexamer to a heterooligomer with far-reaching functional implications (Arumughan et al. 2016). We are constantly developing more powerful methods for the identification and validation of protein-protein interactions, most recently LuTHy, a double readout luminescence-based technology for interactome mapping in mammalian cells (Trepte et al., Mol Syst Biol, 2018).