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

Niko Hensel, Florian Wegner, Susanne Petri, Andreas Hermann, Ludo Van Den Bosch, Jared Sterneckert, Tobias Cantz, Tobias M Boeckers, Peter Reinhardt, Franziska Bursch, Wenting Guo, Julia Japtok, Masin Abo-Rady, Reto Eggenschwiler, Selma Staege, Maximilian Naujock, Norman Kalmbach

Journal: Human molecular genetics 2020;28(17):2835-2850

PMID: 31108504

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Abstract

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.

Address: Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.; Center of Systems Neuroscience, Hannover, Germany.; Research Group Translational Hepatology and Stem Cell Biology, Cluster of Excellence REBIRTH, Hannover Medical School, 30625 Hannover, Germany.; DFG Research Center for Regenerative Therapies.; Division for Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany.; Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), KU Leuven-University of Leuven, BE-3000 Leuven, Belgium.; Laboratory of Neurobiology, VIB-Center for Brain & Disease Research, BE-3000 Leuven, Belgium.; Institute of Neuroanatomy, Hannover Medical School, 30625 Hanover, Germany.; Institute of Anatomy and Cell Biology, Ulm University, 89081 Ulm, Germany.

DOI: 10.1093/hmg/ddz107