Reference : Functional and Molecular Properties of DYT-SGCE Myoclonus-Dystonia Patient-Derived St...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Functional and Molecular Properties of DYT-SGCE Myoclonus-Dystonia Patient-Derived Striatal Medium Spiny Neurons.
Kutschenko, Anna [> >]
Staege, Selma [> >]
Grütz, Karen [> >]
Glaß, Hannes [> >]
Kalmbach, Norman [> >]
Gschwendtberger, Thomas [> >]
Henkel, Lisa M. [> >]
Heine, Johanne [> >]
Grünewald, Anne mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology]
Hermann, Andreas [> >]
Seibler, Philip [> >]
Wegner, Florian [> >]
International journal of molecular sciences
Yes (verified by ORBilu)
[en] 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
[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.
Dystonia Medical Research Foundation

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