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

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.

• Authors: Franziska Bursch, Norman Kalmbach, Maximilian Naujock, Selma Staege, Reto Eggenschwiler, Masin Abo-Rady, Julia Japtok, Wenting Guo, Niko Hensel, Peter Reinhardt, Tobias M Boeckers, Tobias Cantz, Jared Sterneckert, Ludo Van Den Bosch, Andreas Hermann, Susanne Petri, Florian Wegner
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 28 Issue 17 Pg. 2835-2850 (09 01 2019) ISSN: 1460-2083 [Electronic] England
• PMID: 31108504 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Biomarkers
• C9orf72 Protein
• C9orf72 protein, human
• DNA-Binding Proteins
• FUS protein, human
• RNA-Binding Protein FUS
• Receptors, Glutamate
• SOD1 protein, human
• TARDBP protein, human
• Superoxide Dismutase-1
• Calcium

Topics

• Amyotrophic Lateral Sclerosis (diagnosis, genetics, metabolism)
• Biomarkers
• C9orf72 Protein (genetics)
• Calcium (metabolism)
• Calcium Signaling
• DNA-Binding Proteins (genetics)
• Disease Susceptibility
• Genetic Association Studies
• Genetic Predisposition to Disease
• Humans
• Induced Pluripotent Stem Cells (metabolism)
• Motor Neurons (cytology, metabolism)
• Mutation
• Neural Stem Cells (cytology, metabolism)
• RNA-Binding Protein FUS (genetics)
• Receptors, Glutamate (metabolism)
• Superoxide Dismutase-1 (genetics)