Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Human neural networks with sparse TDP-43 pathology reveal NPTX2 misregulation in ALS/FTLD

View ORCID ProfileMarian Hruska-Plochan, Katharina M. Betz, View ORCID ProfileSilvia Ronchi, View ORCID ProfileVera I. Wiersma, Zuzanna Maniecka, Eva-Maria Hock, Florent Laferriere, Sonu Sahadevan, Vanessa Hoop, View ORCID ProfileIgor Delvendahl, Martina Panatta, Alexander van der Bourg, View ORCID ProfileDasa Bohaciakova, View ORCID ProfileKarl Frontzek, View ORCID ProfileAdriano Aguzzi, View ORCID ProfileTammaryn Lashley, View ORCID ProfileMark D. Robinson, Theofanis Karayannis, Martin Mueller, View ORCID ProfileAndreas Hierlemann, View ORCID ProfileMagdalini Polymenidou
doi: https://doi.org/10.1101/2021.12.08.471089
Marian Hruska-Plochan
1Department of Quantitative Biomedicine, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Marian Hruska-Plochan
Katharina M. Betz
1Department of Quantitative Biomedicine, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
2Department of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
3SIB Swiss Institute of Bioinformatics, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Silvia Ronchi
4Department of Biosystems Science and Engineering, ETH Zürich, Mattenstrasse 26, 4058 Basel, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Silvia Ronchi
Vera I. Wiersma
1Department of Quantitative Biomedicine, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Vera I. Wiersma
Zuzanna Maniecka
1Department of Quantitative Biomedicine, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eva-Maria Hock
1Department of Quantitative Biomedicine, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Florent Laferriere
1Department of Quantitative Biomedicine, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sonu Sahadevan
1Department of Quantitative Biomedicine, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Vanessa Hoop
2Department of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Igor Delvendahl
2Department of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Igor Delvendahl
Martina Panatta
1Department of Quantitative Biomedicine, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alexander van der Bourg
5Brain Research Institute, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dasa Bohaciakova
7Department of Histology and Embryology, Faculty of Medicine, Masaryk University Brno, Kamenice 3, 62500, Brno, Czech Republic
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Dasa Bohaciakova
Karl Frontzek
6Institute of Neuropathology, University of Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Karl Frontzek
Adriano Aguzzi
6Institute of Neuropathology, University of Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Adriano Aguzzi
Tammaryn Lashley
8Queen Square Brain Bank for Neurological diseases, Department of Movement Disorders, UCL Institute of Neurology, London, WC1N 1PJ, UK
9Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Tammaryn Lashley
Mark D. Robinson
2Department of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
3SIB Swiss Institute of Bioinformatics, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Mark D. Robinson
Theofanis Karayannis
5Brain Research Institute, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martin Mueller
2Department of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andreas Hierlemann
4Department of Biosystems Science and Engineering, ETH Zürich, Mattenstrasse 26, 4058 Basel, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Andreas Hierlemann
Magdalini Polymenidou
1Department of Quantitative Biomedicine, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Magdalini Polymenidou
  • For correspondence: magdalini.polymenidou@uzh.ch
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Human cellular models of neurodegeneration require reproducibility and longevity, which is necessary for simulating these age-dependent diseases. Such systems are particularly needed for TDP-43 proteinopathies1,2, which involve human-specific mechanisms3–6 that cannot be directly studied in animal models. To explore the emergence and consequences of TDP-43 pathologies, we generated iPSC-derived, colony morphology neural stem cells (iCoMoNSCs) via manual selection of neural precursors7. Single-cell transcriptomics (scRNA-seq) and comparison to independent NSCs8, showed that iCoMoNSCs are uniquely homogenous and self-renewing. Differentiated iCoMoNSCs formed a self-organized multicellular system consisting of synaptically connected and electrophysiologically active neurons, which matured into long-lived functional networks. Neuronal and glial maturation in iCoMoNSC-derived cultures was similar to that of cortical organoids9. Overexpression of wild-type TDP-43 in a minority of iCoMoNSC-derived neurons led to progressive fragmentation and aggregation, resulting in loss of function and neurotoxicity. scRNA-seq revealed a novel set of misregulated RNA targets coinciding in both TDP-43 overexpressing neurons and patient brains exhibiting loss of nuclear TDP-43. The strongest misregulated target encoded for the synaptic protein NPTX2, which was consistently misaccumulated in ALS and FTLD patient neurons with TDP-43 pathology. Our work directly links TDP-43 misregulation and NPTX2 accumulation, thereby highlighting a new pathway of neurotoxicity.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Back to top
PreviousNext
Posted December 09, 2021.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Human neural networks with sparse TDP-43 pathology reveal NPTX2 misregulation in ALS/FTLD
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Human neural networks with sparse TDP-43 pathology reveal NPTX2 misregulation in ALS/FTLD
Marian Hruska-Plochan, Katharina M. Betz, Silvia Ronchi, Vera I. Wiersma, Zuzanna Maniecka, Eva-Maria Hock, Florent Laferriere, Sonu Sahadevan, Vanessa Hoop, Igor Delvendahl, Martina Panatta, Alexander van der Bourg, Dasa Bohaciakova, Karl Frontzek, Adriano Aguzzi, Tammaryn Lashley, Mark D. Robinson, Theofanis Karayannis, Martin Mueller, Andreas Hierlemann, Magdalini Polymenidou
bioRxiv 2021.12.08.471089; doi: https://doi.org/10.1101/2021.12.08.471089
Reddit logo Twitter logo Facebook logo LinkedIn logo Mendeley logo
Citation Tools
Human neural networks with sparse TDP-43 pathology reveal NPTX2 misregulation in ALS/FTLD
Marian Hruska-Plochan, Katharina M. Betz, Silvia Ronchi, Vera I. Wiersma, Zuzanna Maniecka, Eva-Maria Hock, Florent Laferriere, Sonu Sahadevan, Vanessa Hoop, Igor Delvendahl, Martina Panatta, Alexander van der Bourg, Dasa Bohaciakova, Karl Frontzek, Adriano Aguzzi, Tammaryn Lashley, Mark D. Robinson, Theofanis Karayannis, Martin Mueller, Andreas Hierlemann, Magdalini Polymenidou
bioRxiv 2021.12.08.471089; doi: https://doi.org/10.1101/2021.12.08.471089

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Neuroscience
Subject Areas
All Articles
  • Animal Behavior and Cognition (4239)
  • Biochemistry (9172)
  • Bioengineering (6804)
  • Bioinformatics (24064)
  • Biophysics (12155)
  • Cancer Biology (9564)
  • Cell Biology (13825)
  • Clinical Trials (138)
  • Developmental Biology (7658)
  • Ecology (11737)
  • Epidemiology (2066)
  • Evolutionary Biology (15541)
  • Genetics (10672)
  • Genomics (14359)
  • Immunology (9511)
  • Microbiology (22901)
  • Molecular Biology (9129)
  • Neuroscience (49113)
  • Paleontology (357)
  • Pathology (1487)
  • Pharmacology and Toxicology (2583)
  • Physiology (3851)
  • Plant Biology (8351)
  • Scientific Communication and Education (1473)
  • Synthetic Biology (2301)
  • Systems Biology (6205)
  • Zoology (1302)