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Open AccessArticle

Functional and Molecular Properties of DYT-SGCE Myoclonus-Dystonia Patient-Derived Striatal Medium Spiny Neurons

1
Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
2
Center for Systems Neuroscience, Bünteweg 2, 30559 Hannover, Germany
3
Institute of Neurogenetics, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
4
Translational Neurodegeneration Section “Albrecht-Kossel“, Department of Neurology, University Medical Center, University of Rostock, Gehlsheimer Str. 20, 18147 Rostock, Germany
5
German Center for Neurodegenerative Diseases Rostock/Greifswald, 18147 Rostock, Germany
6
Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center, University of Rostock, 18147 Rostock, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Rivka Ofir
Int. J. Mol. Sci. 2021, 22(7), 3565; https://doi.org/10.3390/ijms22073565
Received: 19 February 2021 / Revised: 18 March 2021 / Accepted: 24 March 2021 / Published: 30 March 2021
(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery 2.0)
Myoclonus-dystonia (DYT-SGCE, formerly DYT11) is characterized by alcohol-sensitive, myoclonic-like appearance of fast dystonic movements. It is caused by mutations in the SGCE gene encoding ε-sarcoglycan leading to a dysfunction of this transmembrane protein, alterations in the cerebello-thalamic pathway and impaired striatal plasticity. To elucidate underlying pathogenic mechanisms, we investigated induced pluripotent stem cell (iPSC)-derived striatal medium spiny neurons (MSNs) from two myoclonus-dystonia patients carrying a heterozygous mutation in the SGCE gene (c.298T>G and c.304C>T with protein changes W100G and R102X) in comparison to two matched healthy control lines. Calcium imaging showed significantly elevated basal intracellular Ca2+ content and lower frequency of spontaneous Ca2+ signals in SGCE MSNs. Blocking of voltage-gated Ca2+ channels by verapamil was less efficient in suppressing KCl-induced Ca2+ peaks of SGCE MSNs. Ca2+ amplitudes upon glycine and acetylcholine applications were increased in SGCE MSNs, but not after GABA or glutamate applications. Expression of voltage-gated Ca2+ channels and most ionotropic receptor subunits was not altered. SGCE MSNs showed significantly reduced GABAergic synaptic density. Whole-cell patch-clamp recordings displayed elevated amplitudes of miniature postsynaptic currents and action potentials in SGCE MSNs. Our data contribute to a better understanding of the pathophysiology and the development of novel therapeutic strategies for myoclonus-dystonia. View Full-Text
Keywords: DYT-SGCE; myoclonus-dystonia; induced pluripotent stem cells; striatal medium spiny neurons; calcium dynamics; patch-clamp electrophysiology; GABAergic synaptic density DYT-SGCE; myoclonus-dystonia; induced pluripotent stem cells; striatal medium spiny neurons; calcium dynamics; patch-clamp electrophysiology; GABAergic synaptic density
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MDPI and ACS Style

Kutschenko, A.; Staege, S.; Grütz, K.; Glaß, H.; Kalmbach, N.; Gschwendtberger, T.; Henkel, L.M.; Heine, J.; Grünewald, A.; Hermann, A.; Seibler, P.; Wegner, F. Functional and Molecular Properties of DYT-SGCE Myoclonus-Dystonia Patient-Derived Striatal Medium Spiny Neurons. Int. J. Mol. Sci. 2021, 22, 3565. https://doi.org/10.3390/ijms22073565

AMA Style

Kutschenko A, Staege S, Grütz K, Glaß H, Kalmbach N, Gschwendtberger T, Henkel LM, Heine J, Grünewald A, Hermann A, Seibler P, Wegner F. Functional and Molecular Properties of DYT-SGCE Myoclonus-Dystonia Patient-Derived Striatal Medium Spiny Neurons. International Journal of Molecular Sciences. 2021; 22(7):3565. https://doi.org/10.3390/ijms22073565

Chicago/Turabian Style

Kutschenko, Anna; Staege, Selma; Grütz, Karen; Glaß, Hannes; Kalmbach, Norman; Gschwendtberger, Thomas; Henkel, Lisa M.; Heine, Johanne; Grünewald, Anne; Hermann, Andreas; Seibler, Philip; Wegner, Florian. 2021. "Functional and Molecular Properties of DYT-SGCE Myoclonus-Dystonia Patient-Derived Striatal Medium Spiny Neurons" Int. J. Mol. Sci. 22, no. 7: 3565. https://doi.org/10.3390/ijms22073565

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