Objective: What are the underlying pathological mechanisms of myoclonus dystonia (DYT-SGCE)?

Background: Myoclonus dystonia (DYT-SGCE, DYT11) is a combined dystonia characterized by alcohol-sensitive myoclonic-like appearance of fast dystonic movements and autosomal dominant inheritance. Myoclonus dystonia is caused by mutations in the maternally imprinted gene encoding ε-sarcoglycan (SGCE) leading to a dysfunction of a widely expressed transmembrane protein. It is suggested that alterations in the GABAergic system lead to dysfunction of the cerebello-thalamic pathway and impaired striatal plasticity.

Method: To investigate pathophysiological mechanisms, human induced pluripotent stem cell (iPSC)-derived medium spiny neurons (MSNs) from two patients carrying a heterozygous mutation in the gene SGCE (SGCE,c.298T>G and SGCE,c.304C>T) are functionally investigated to explore an associated neuronal phenotype. Electrophysiological analysis using calcium imaging and whole-cell patch-clamp recordings are used to analyze neuronal function as well as synaptic activity to identify disease-relevant phenotypes linked to dystonia compared to MSNs derived from two healthy controls.

Results: After 70 days of differentiation, comparable large populations of GABAergic neurons and DARPP32-positive striatal MSNs were found in SGCE and control MSNs.First results show significantly increased intracellular calcium content at the basal level and in response to acetylcholine in SGCE MSNs. However, the expression of GABA_A receptor subunits and nicotinic acetylcholine receptor subunits in SGCE MSNs are not altered. SGCE and control MSNs showed similar potassium and sodium inward currents and spontaneous action potentials (APs), but spontaneous synaptic activity revealed higher amplitudes of postsynaptic currents in SGCE MSNs.

Conclusion: The intervention of specific anti-cholinergic substances and other promising substances will be further assessed to explore associated pathological mechanisms in myoclonus dystonia. The in vitro modelling of this disease using iPSC-derived medium spiny neurons can contribute to identify potential drug targets for novel therapeutic strategies in dystonia with SGCE mutations.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/development-of-novel-treatment-strategies-for-sgce-dystonia-using-patient-derived-induced-pluripotent-stem-cells-ipscs/