Dominik Paquet – iPSC-models of brain diseases
The PaquetLab aims to understand the molecular and cellular mechanisms leading to nerve cell death and cognitive decline in patients with neuropsychiatric disorders (e.g. Alzheimer’s disease, Frontotemporal dementia and related disorders) and neurovascular impairments (stroke and vascular cognitive impairment). We apply cutting-edge technologies, such as CRISPR/Cas genome editing, differentiation of induced pluripotent stem cells (iPSCs) into human brain cells, and tissue engineering to build advanced human in vitro model systems recapitulating disease.
Due to the inaccessibility of human brain cells for molecular research, neurodegenerative diseases have mostly been studied in animal and simplified cellular models, which have significantly broadened our knowledge, but have drawbacks limiting successful translational research. We aim to address this gap by developing human model systems based on iPSCs, which have the genetic configuration of patients. iPSCs allow differentiating and studying somatic brain cell types directly affected by disease, such as neurons, astrocytes, microglia, oligodendrocytes, smooth muscle cells and endothelial cells.
We have recently established protocols for the optimized differentiation of major cell types of the human brain, and also developed efficient technologies to introduce and remove patient mutations using CRISPR/Cas genome editing. In a recent study (Paquet et al. Nature 2016) we have already demonstrated the potential and feasibility of our approach, by generating and studying isogenic sets of human cortical neurons with mutations in the Alzheimer-associated genes. These APP- and PSEN1- mutant neurons displayed Alzheimer-related symptoms.
We aim to extend this work by generating all major cell types relevant for neurodegenerative or neurovascular disease in the human brain from iPSCs, and combining them in a human brain tissue model. In this artificial human brain tissue we aim to elicit and study disease phenotypes and investigate underlying mechanisms. In addition, because such models are accessible for genetic manipulation and amenable to drug development, we plan to apply them for translational studies to accelerate the identification of novel therapeutic approaches and targets.
Professor of Neurobiology
Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich
Room 8G 02 144
D-81377 Munich, Germany
Phone: +49 89 4400 46123
Dominik Paquet, Dylan Kwart, Antonia Chen, Andrew Sproul, Samson Jacob, Shaun Teo, Kimberly Moore Olsen, Andrew Gregg, Scott Noggle, Marc Tessier-Lavigne (2016) Efficient introduction of specific homozygous and heterozygous mutations using CRISPR/Cas9. Nature 533: 7601. 125-129 May.
Peter Engerer, Gabriela Plucinska, Rachel Thong, Laura Trovò, Dominik Paquet, Leanne Godinho (2016) Imaging Subcellular Structures in the Living Zebrafish Embryo. Journal of visualized experiments : JoVE 110. Apr.
Julien Giustiniani, Béatrice Chambraud, Elodie Sardin, Omar Dounane, Kevin Guillemeau, Hiroko Nakatani, Dominik Paquet, Amina Kamah, Isabelle Landrieu, Guy Lippens, Etienne-Emile Baulieu, Marcel Tawk (2014) Immunophilin FKBP52 induces Tau-P301L filamentous assembly in vitro and modulates its activity in a model of tauopathy. Proceedings of the National Academy of Sciences of the United States of America 111: 12. 4584-4589 Mar.
Gabriela Plucińska, Dominik Paquet, Alexander Hruscha, Leanne Godinho, Christian Haass, Bettina Schmid, Thomas Misgeld (2012) In vivo imaging of disease-related mitochondrial dynamics in a vertebrate model system. The Journal of neuroscience : the official journal of the Society for Neuroscience 32: 46. 16203-16212 Nov.
Mareike E Fett, Anna Pilsl, Dominik Paquet, Frauke van Bebber, Christian Haass, Jörg Tatzelt, Bettina Schmid, Konstanze F Winklhofer (2010) Parkin is protective against proteotoxic stress in a transgenic zebrafish model. PloS one 5: 7. Jul.
Frauke van Bebber, Dominik Paquet, Alexander Hruscha, Bettina Schmid, Christian Haass (2010) Methylene blue fails to inhibit Tau and polyglutamine protein dependent toxicity in zebrafish. Neurobiology of disease 39: 3. 265-271 Sep.
Dominik Paquet, Bettina Schmid, Christian Haass (2010) Transgenic zebrafish as a novel animal model to study tauopathies and other neurodegenerative disorders in vivo. Neuro-degenerative diseases 7: 1-3. 99-102 Feb.
Dominik Paquet, Ratan Bhat, Astrid Sydow, Eva-Maria Mandelkow, Stefan Berg, Sven Hellberg, Johanna Fälting, Martin Distel, Reinhard W Köster, Bettina Schmid, Christian Haass (2009)
A zebrafish model of tauopathy allows in vivo imaging of neuronal cell death and drug evaluation. The Journal of clinical investigation 119: 5. 1382-1395 May.
Nicole Exner, Bettina Treske, Dominik Paquet, Kira Holmström, Carola Schiesling, Suzana Gispert, Iria Carballo-Carbajal, Daniela Berg, Hans-Hermann Hoepken, Thomas Gasser, Rejko Krüger, Konstanze F Winklhofer, Frank Vogel, Andreas S Reichert, Georg Auburger, Philipp J Kahle, Bettina Schmid, Christian Haass (2007) Loss-of-function of human PINK1 results in mitochondrial pathology and can be rescued by parkin. The Journal of neuroscience : the official journal of the Society for Neuroscience 27: 45. 12413-12418 Nov.
Dominik Paquet, Principal investigator
Dominik established the PaquetLab at ISD in 2017, after he was appointed Professor for Neurobiology at LMU Munich and became a member of the Munich Cluster for Systems Neurology (SyNergy). He received his BSc and MSc from the Eberhard-Karls-University Tübingen, Germany. During his MSc Dominik worked with Henry Roehl at the MRC Centre for Developmental Genetics in Sheffield, UK. For his PhD, Dominik developed the first Tau-transgenic zebrafish model to study mechanisms of Tau-related neurodegeneration with Christian Haass at LMU Munich. After working with Thomas Misgeld at TU Munich for 2 years on in vivo imaging to study mitochondrial transport defects in neurodegenerative diseases, Dominik joined the lab of Marc Tessier-Lavigne at The Rockefeller University in NYC as a New York Stem Cell Foundation Druckenmiller Fellow. There, he pioneered the use of CRISPR/Cas9 gene editing in induced pluripotent stem cells to study diseases of the human brain.
E-Mail: email@example.com Phone: +49 89 440046123
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Andrea Stüven, Team Assistant
Andrea joined the PaquetLab in May 2018 after having shared time with her family for some years, living abroad and working for another research institute at LMU. She supports the research team in multiple ways with her work experience and appreciates learning new things every day. When not at work she enjoys going to the opera and concerts, visiting art exhibitions, working in her garden and swimming. She also tries to stay connected with family and friends from across the world as much as possible.
E-Mail: firstname.lastname@example.org Phone: +49 89 440046026
Julien Klimmt, GSN graduate student
Julien was born and raised in Chemnitz, Germany. He received his BSc in Human Biology from the University of Greifswald in 2014 and a MSc in Molecular Biosciences with a major in neurosciences at the University of Heidelberg. During his Master’s he worked at Harvard Medical School with Dr. Matthew J. LaVoie on the cytosolic function of Parkin. In 2017 he finished his Master’s degree working on epigenetic mechanisms in memory formation and then joined the PaquetLab as a graduate student. He is now working on complex cell culture systems using CRISPR/Cas9-edited, iPSC-derived brain cells to model AD.
E-Mail: email@example.com Phone: +49 89 440046223
Isabel Weisheit, GSN graduate student
Isabel grew up in Augsburg, Germany. She obtained her BSc in Biochemistry from the University of Ulm and her MSc from LMU Munich. For her master’s thesis she joined the group of Prof. Jernej Ule at the Francis Crick Institute in London, where she studied the RNA-binding properties of TDP-43. Isabel started in the PaquetLab in April 2017 as a graduate student and is focusing on using CRISPR/Cas9-edited iPSCs to establish in vitro models of vascular dysfunction.
E-Mail: firstname.lastname@example.org Phone: +49 89 440046222
Dennis Crusius, BTA
Dennis is from Munich, where he also obtained his BTA degree. He joined the PaquetLab as a research assistant in November 2017 and is involved in several projects from stem cell differentiation to CRISPR/Cas9 genome editing. He also contributes to a functional lab environment and supports the entire team in multiple ways.
E-Mail: email@example.com Phone: +49 89 440046224
Angelika Dannert, GSN graduate student
Angelika grew up near Ulm in Germany. She studied Molecular Medicine and obtained her BSc from the University of Tübingen, and her MSc from the University of Göttingen, Germany. During her studies she did international research internships at Free University Amsterdam, University of Zürich, and Stanford University. During her master’s she worked on iPSC-based models of depression followed by her thesis on prevention of vascular stiffening. She joined the PaquetLab in December 2018 and is working on the development of complex in vitro models of FTD using CRISPR/Cas9-edited iPSC-derived brain cells.
E-Mail: firstname.lastname@example.org Phone: +49 89 440046223
Judit Gonzalez Gallego, GSN graduate student, collaboration with DichgansLab, ISD
Judit is a native of Spain. She obtained her BSc in biochemistry from the Autonomous University of Barcelona. After completing her bachelors degree, she worked for one year at the Center of Neurobiology of Hamburg University with Dr. Marina Mikhaylova in protein neuronal transport. Currently, she is a fast-track student in the Graduate School of Systemic Neuroscience (GSN) and after performing a research internship in PaquetLab on CRISPR/Cas9 genome editing she decided to join the ISD in October 2018 for a PhD project in neurovascular disorders co-supervised by Martin Dichgans and Dominik Paquet.
E-Mail: email@example.com Phone: +49 89 440046177
Liliana Pedro, GSN graduate student, collaboration with Simons Lab, DZNE
Liliana was born in Portugal. She received her BSc in Biochemistry (2011) and her MSc in Molecular Biotechnology (2013) from the University of Aveiro, Portugal. For her Master Thesis she worked to establish the role of trace elements in the structure and metabolism of connective tissues at the Medical Research Council in Cambridge, UK. After her Master, she remained in Cambridge working as a research assistant applying her expertise in the optical emission spectroscopy analysis of biological samples. In 2015 she joined Prof. Ulrike Gaul lab at the Gene Center in Munich investigating the blood brain barrier development in Drosophila melanogaster. At the moment she doing her PhD in Prof. Mikael Simons group, studying oligodendrocyte myelination in development and adults, in a collaborative project with the PaquetLab.
E-Mail: Liliana.Pedro-Domingues@dzne.de Phone: +49 89 440046480
Joseph Kroeger, GSN master student, collaboration with DichgansLab, ISD
Joseph grew up in the U.S. state of North Carolina. He earned a BSc in mathematics and chemistry with minors in physics and philosophy from Wingate University. After graduating from Wingate University, he moved to Munich and became a master’s student with the GSN. For his master’s thesis, he is working on approaches to apply CRISPR/Cas genomic editing to investigate the role of stroke-associated genes in iPSC-derived models.
E-Mail: Joseph.Kroeger@med-uni-muenchen.de Phone: +49 89 440046480
Sophie Robinson, GSN undergraduate researcher, collaboration with Haass Lab, DZNE
Sophie is from the Bay Area in California, USA. She received her BSc in Psychology and Biological Sciences from Carnegie Mellon University. In high school, she had internships at Stanford University with Dr. Tony Wyss-Coray studying AD. During her Bachelor's, she worked with Dr. Stephen Strittmatter at Yale University investigating a Fyn kinase inhibitor as a potential treatment in AD mouse models, which has subsequently made it into clinical trials. After graduating from college, she worked in a cancer immunotherapy lab under Dr. Ron Levy at Stanford University and in clinical operations at Roche Genentech. Sophie is a GSN Fast-Track student and started a rotation at the PaquetLab in February 2019. She is interested in studying microglia in homeostatic and disease-associated states, co-supervised by Christian Haass and Dominik Paquet.
E-Mail: Sophie.Robinson@med-uni-muenchen.de Phone: +49 89 440046480
Ioanna Emmanouilidis, GSN undergraduate researcher, collaboration with DichgansLab, ISD
Ioanna was born and raised in Athens, Greece. She received her BSc on Life Sciences from Pierre and Marie Curie University in Paris in 2018. During her undergraduate studies, she spent a semester at Karolinska Institut in Stockholm where she did a research internship on insulin signaling and genetic risk factors related to Alzheimer’s disease. Currently, she is a first-year master’s student at the Graduate School of Systemic Neurosciences (GSN-LMU) and works on the role of stroke-associated genes in iPSC-derived models.
E-Mail: Ioanna.Emmanouilidis@med-uni-muenchen.de Phone: +49 89 440046480
Sarah Hübner, undergraduate researcher
Sarah was born in Augsburg, Germany. After completing her BSc in Chemistry and Biochemistry at LMU Munich, she did a research internship at University of California Berkeley. There, she worked with Prof. Evan W. Miller on voltage-sensitive fluorescent dyes and also joined the lab of Prof. Christopher J. Chang developing fluorescent copper(I) sensors. Currently, she proceeds with her master’s studies at LMU Munich. She joined the PaquetLab in April 2018 to study CRISPR/Cas9 edited iPSCs as a model system for neurovascular disorders.
Johannes Heim, undergraduate researcher
Johannes comes from a small town in the south of Munich. He studies medicine at LMU Munich. During the preclinical stage of his studies he did an internship in molecular neurophysiology in Prof. Michael Meyers Lab at LMU Munich. With an intrinsic interest in neurology and vascular medicine, he gained experience in these fields during clinical electives. Johannes worked on a collaborative project between the DichgansLab and PaquetLab to investigate the role of endothelial cells in ischemic stroke.
I have a long-standing interest in elucidating the molecular mechanisms leading to degeneration of the human brain in Alzheimer’s disease (AD), frontotemporal dementia (FTD), stroke and related neurodegenerative and neurovascular disorders. One of the major research goals of my lab is to develop model systems that recapitulate central features of human disease and apply these models to investigate the molecular players leading to malfunction and demise of neurons. I started my scientific career as a graduate student with Christian Haass at LMU Munich, where I developed the first transgenic zebrafish model of AD and FTD that showed neurodegeneration and protein aggregation. I a follow-up study with Thomas Misgeld at TU Munich we performed the first in vivo imaging of axonal transport, a cellular pathway involved in disease progression, in an intact vertebrate animal. Both studies opened the field for human disease modelling in transgenic zebrafish, served as models for several subsequent studies in other labs, were highly cited (Publications in JCI and J Neuroscience), and received several research awards.
After focusing on animal models during my PhD, I moved closer to the human patient during my Postdoc with Marc Tessier-Lavigne at The Rockefeller University in NYC. There, I developed induced pluripotent stem cell (iPSC) based models of Alzheimer’s disease (AD) and Tauopathies in collaboration with scientists at the New York Stem Cell Foundation. At this point, first studies had described the use of patient iPSCs for AD disease modelling, but there was no technology available allowing efficient genetic access, to introduce or correct mutations. I developed robust techniques for genome editing of iPSCs using CRISPR/Cas9 and demonstrated for the first time the formation of disease-relevant, zygosity-dependent phenotypes by knock-in two early-onset AD mutations (Publications in Nature and Nature Protocols).
Based on this work, my lab at ISD Munich is now focussing on building advanced human in vitro model systems recapitulating neurodegenerative and neurovascular diseases using iPSCs and genome editing with CRISPR/Cas9.
Scientific vita | Dominik Paquet
2011 – 2016 Postdoctoral Fellow, Laboratory for Brain Development and Repair, The Rockefeller University, New York, USA; Mentor: Marc Tessier-Lavigne
2009 – 2011 Postdoctoral Fellow, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Mentors: Thomas Misgeld, Christian Haass
2005 – 2009 PhD Thesis (summa cum laude), Department of Biochemistry, Adolf-Butenandt-Institute, Ludwig-Maximilians University (LMU), Munich, Germany; Mentor: Christian Haass
2004 – 2005 Diploma Thesis, MRC Centre for Developmental Genetics, University of Sheffield, United Kingdom; Mentor: Henry Roehl
1999 – 2004 Studies of Biology (summa cum laude), University of Tuebingen, Germany
• Druckenmiller Postdoctoral Fellowship, The New York Stem Cell Foundation
• Postdoctoral Fellowship, German Academy of Sciences Leopoldina
• PhD-Fellowship, Universität Bayern e.V. (Graduiertenförderung nach dem Bayerischen Eliteförderungsgesetz)
• Diploma Thesis Fellowship, German academic exchange service (DAAD)
• Diploma Thesis Fellowship, Department of Biomedical Sciences, University of Sheffield, UK
• Best poster award, The New York Stem Cell Foundation Innovators Retreat 2016
• Best talk award, The New York Stem Cell Foundation Innovators Retreat 2015
• Award for 'Intelligible Science’, Helmholtz Zentrum Geesthacht, 2010
• Finalist at Deutscher Studienpreis 2010, Körber-Stiftung, 2010
• Best talk award, Interact-Meeting Munich 2009
• International Leda-Hanin-Award of the Cornelli Foundation, AD/PD-Meeting 2009
• International Verum Award of the Verum Foundation, 2009
• 1st Young Investigator Award of the Universität Bayern e.V., 2008
• Travel award, The Lindau Nobel Laureate Meeting, 2007
22 Oct 2018
We used the great fall weather for a lab hiking trip to Brecherspitze in the Bavarian Alps. It was a great day, and everyone had a lot of fun.
11 Oct 2018
Dominik visited Dirk Busch and colleagues at TUM Institute for Immunology in Munich for a talk and discussions about CRISPR genome editing.
29 Sep 2018
We had a great night at the Oktoberfest in Munich - everyone had a lot of fun!
20 Sep 2018
Dominik joined the Meeting of the German Society for Biochemistry and Molecular Biology in Marburg to talk about our most recent work in CRISPR genome editing and iPSC disease modeling! Thanks GBM for the invitation!
4 Aug 2018
We just finished our first molecular neurobiology course for the GSN - Graduate school of Systemic Neurosciences. The students learned how to turn human iPSCs into cortical neurons and took a couple of cool pictures of their cells. Looking forward to next year!
3 Aug 2018
We had our first PaquetLab barbecue! It was a great night with steaks, drinks and star-gazing :-)
18 Jul 2018
Go @PaquetLab! We had great fun with 40.000 other runners at the Olympic stadium in Munich at b2run, one of the biggest running events for company teams in Germany, and we supported the winning team of our LMU University hospital.
11 Jul 2018
Isabel and Julien received awards for the beautiful images they submitted to the photo competition at the ISD retreat in Herrsching, Germany. Congrats!
26 Jun 2018
1 May 2018
Dominik visited the Instituto de Technologia Quimica e Biologica in Lisbon to help with a PhD defense and give a talk about CRISPR genome editing. Many thanks to Catarina Brito and Claudia Almeida for the kind invitation!
30 Apr 2018
Sarah and Johannes joined the PaquetLab for research projects on neurodegenerative and neurovascular disorders, welcome!
15 Apr 2018
Dominik our work on genome editing and Alzheimer disease modeling in iPSCs at the CTERP translational research in cell therapy meeting in Moscow, Russia.
15 Jan 2018
Judit joined the PaquetLab for an undergraduate research project on CRISPR/Cas9 genome editing, welcome!
19 Dec 2017
Dominik invited the whole team to his place for the annual Christmas party. Everybody was so busy eating and drinking that we didn’t take any pictures.
12 Dec 2017
PaquetLab goes Christmas Market! We had a great time (and great Glühwein and food) at the traditional market in Haidhausen.
01 Nov 2017
Dennis joins the PaquetLab as BTA and will support us in multiple ways in the cell culture and general lab. Welcome aboard Dennis!
27 Oct 2017
05 Sep 2017
Our work on improving HDR efficiency for CRISPR Editing is featured on the Addgene Blog. Thanks to Dylan Kwart at The Rockefeller University and Tyler Ford at Addgene for the nice collaboration.
01 Sep 2017
After several weeks of construction, we opened our new stem cell research facility at the CSD building. The new lab provides ideal conditions to grow and characterize novel human brain tissue models derived from patient stem cells, to investigate molecular mechanisms of dementia, stroke and related diseases.
16 Jun 2017
16 Jun 2017
16 Jun 2017
Dominik presents our work at Evotec AG in Hamburg, Germany.
03 Apr 2017
Welcome to Julien, who also joined the lab as a graduate student - we look forward to working with you!
03 Apr 2017
Welcome to Isabel, who joined the lab as a graduate student - we look forward to working with you!
31 Mar 2017
01 Dec 2016
Coming from The Rockefeller University (New York, USA), Dominik Paquet has joined the ISD. He was appointed Professor for Neurobiology and is a member of the Munich Cluster for Systems Neurology (SyNergy). Following his PhD at the LMU Munich, Prof. Paquet worked as a New York Stem Cell Foundation Druckenmiller Fellow in the laboratory of Marc Tessier-Lavigne, where he pioneered the use of CRISPR/Cas9 gene editing in induced pluripotent stem cells to study diseases of the human brain. His research at the ISD will center on the molecular and cellular mechanisms leading to neuronal death and cognitive decline in patients with neuropsychiatric disorders (e.g. Alzheimer’s disease and Frontotemporal dementia) and neurovascular impairments (stroke and vascular cognitive impairment). He plans to build advanced human in vitro model systems based on patient-derived cells that recapitulate major disease hallmarks, and thus facilitate molecular studies and accelerate the identification of novel therapeutic approaches.
The PaquetLab is part of the Institute for Stroke and Dementia Research (ISD) and located on the 2nd floor of the new CSD building on the high-tech campus Grosshadern / Martinsried, one of the biggest European centers combining basic and clinical life science research and technological innovation. The campus houses the LMU Klinikum, one of the biggest University hospitals in Europe, several research institutes of the LMU in medical and natural sciences, the Max Planck Institutes for Biochemistry and Neurobiology, as well as the Innovation and Start Up Center for Biotechnology.
Photo: Center for Stroke and Dementia Research © Stefan Müller-Naumann
The CSD building was opened in 2014 and houses research labs of the ISD, the Chair of Metabolic Chemistry of the Medical Faculty of the LMU, the Technical University Munich and the German Center for Neurodegenerative Diseases (DZNE) , an outpatient clinic for stroke and dementia patients, as well as lecture halls, seminar rooms etc. It provides home to over 200 basic and clinician scientists, technical and support stuff.
PaquetLab writing area
Gel area and confocal microscope
Stem cell culture