Article (Scientific journals)
Functional and Molecular Properties of DYT-SGCE Myoclonus-Dystonia Patient-Derived Striatal Medium Spiny Neurons.
Kutschenko, Anna; Staege, Selma; Grütz, Karen et al.
2021In International Journal of Molecular Sciences, 22 (7)
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Keywords :
Acetylcholine/pharmacology; Action Potentials; Adult; Calcium Channel Blockers/pharmacology; Calcium Channels, L-Type/metabolism; Calcium Signaling; Cell Differentiation/physiology; Cells, Cultured; Corpus Striatum/pathology; Dendritic Spines/drug effects/metabolism/pathology; Dystonic Disorders/pathology; Female; Gene Expression; Glycine/pharmacology; Humans; Induced Pluripotent Stem Cells/cytology/physiology; Male; Mecamylamine/pharmacology; Middle Aged; Patch-Clamp Techniques; DYT-SGCE; GABAergic synaptic density; calcium dynamics; induced pluripotent stem cells; myoclonus-dystonia; patch-clamp electrophysiology; striatal medium spiny neurons
Abstract :
[en] 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 Ca(2+) content and lower frequency of spontaneous Ca(2+) signals in SGCE MSNs. Blocking of voltage-gated Ca(2+) channels by verapamil was less efficient in suppressing KCl-induced Ca(2+) peaks of SGCE MSNs. Ca(2+) amplitudes upon glycine and acetylcholine applications were increased in SGCE MSNs, but not after GABA or glutamate applications. Expression of voltage-gated Ca(2+) 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Kutschenko, Anna
Staege, Selma
Grütz, Karen
Glaß, Hannes
Kalmbach, Norman
Gschwendtberger, Thomas
Henkel, Lisa M.
Heine, Johanne
Grünewald, Anne  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology
Hermann, Andreas
Seibler, Philip
Wegner, Florian
External co-authors :
yes
Language :
English
Title :
Functional and Molecular Properties of DYT-SGCE Myoclonus-Dystonia Patient-Derived Striatal Medium Spiny Neurons.
Publication date :
2021
Journal title :
International Journal of Molecular Sciences
ISSN :
1422-0067
Publisher :
Multidisciplinary Digital Publishing Institute (MDPI), Switzerland
Volume :
22
Issue :
7
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
Dystonia Medical Research Foundation
Available on ORBilu :
since 11 November 2021

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