Altered calcium dynamics and glutamate receptor properties in iPSC-derived motor neurons from ALS patients with C9orf72, FUS, SOD1 or TDP43 mutations

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung


  • Franziska Bursch - , Leibniz Universität Hannover (LUH), Stiftung Tierärztliche Hochschule Hannover (TiHo) (Autor:in)
  • Norman Kalmbach - , Leibniz Universität Hannover (LUH) (Autor:in)
  • Maximilian Naujock - , Leibniz Universität Hannover (LUH) (Autor:in)
  • Selma Staege - , Leibniz Universität Hannover (LUH), Stiftung Tierärztliche Hochschule Hannover (TiHo) (Autor:in)
  • Reto Eggenschwiler - , Leibniz Universität Hannover (LUH) (Autor:in)
  • Masin Abo-Rady - , Technische Universität Dresden (Autor:in)
  • Julia Japtok - , Technische Universität Dresden (Autor:in)
  • Wenting Guo - , KU Leuven, Flanders Institute for Biotechnology (VIB) (Autor:in)
  • Niko Hensel - , Leibniz Universität Hannover (LUH) (Autor:in)
  • Peter Reinhardt - , Leibniz Universität Hannover (LUH), Technische Universität Dresden (Autor:in)
  • Tobias M. Boeckers - , Universität Ulm, AbbVie, Universität Rostock (Autor:in)
  • Tobias Cantz - , Leibniz Universität Hannover (LUH) (Autor:in)
  • Jared Sterneckert - , Center for Regenerative Therapies Dresden (CRTD) (Autor:in)
  • Ludo Van Den Bosch - , KU Leuven, Flanders Institute for Biotechnology (VIB) (Autor:in)
  • Andreas Hermann - , Technische Universität Dresden (Autor:in)
  • Susanne Petri - , Leibniz Universität Hannover (LUH), Stiftung Tierärztliche Hochschule Hannover (TiHo) (Autor:in)
  • Florian Wegner - , Leibniz Universität Hannover (LUH), Stiftung Tierärztliche Hochschule Hannover (TiHo) (Autor:in)


The fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS) is characterized by a profound loss of motor neurons (MNs). Until now only riluzole minimally extends life expectancy in ALS, presumably by inhibiting glutamatergic neurotransmission and calcium overload of MNs. Therefore, the aim of this study was to investigate the glutamate receptor properties and key aspects of intracellular calcium dynamics in induced pluripotent stem cell (iPSC)-derived MNs from ALS patients with C9orf72 (n = 4 cell lines), fused in sarcoma (FUS) (n = 9), superoxide dismutase 1 (SOD1) (n = 3) or transactive response DNA-binding protein 43 (TDP43) (n = 3) mutations as well as healthy (n = 7 cell lines) and isogenic controls (n = 3). Using calcium imaging, we most frequently observed spontaneous transients in mutant C9orf72 MNs. Basal intracellular calcium levels and α-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-induced signal amplitudes were elevated in mutant TDP43 MNs. Besides, a majority of mutant TDP43 MNs responded to 3.5-dihydroxyphenylglycine as metabotropic glutamate receptor agonist. Quantitative real-Time PCR demonstrated significantly increased expression levels of AMPA and kainate receptors in mutant FUS cells compared to healthy and isogenic controls. Furthermore, the expression of kainate receptors and voltage gated calcium channels in mutant C9orf72 MNs as well as metabotropic glutamate receptors in mutant SOD1 cells was markedly elevated compared to controls. Our data of iPSC-derived MNs from familial ALS patients revealed several mutation-specific alterations in glutamate receptor properties and calcium dynamics that could play a role in ALS pathogenesis and may lead to future translational strategies with individual stratification of neuroprotective ALS treatments.


Seiten (von - bis)2835-2850
FachzeitschriftHuman molecular genetics
PublikationsstatusVeröffentlicht - 1 Sept. 2019

Externe IDs

PubMed 31108504
ORCID /0000-0002-7688-3124/work/142250024


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