Deciphering the Pathophysiological Mechanisms Underpinning Myoclonus Dystonia Using Pluripotent Stem Cell-Derived Cellular Models

TL;DR

This review explores how stem cell-derived models can help understand the causes and mechanisms of Myoclonus Dystonia, a type of movement disorder.

Contribution

The paper highlights the use of pluripotent stem cells to model Myoclonus Dystonia and study its underlying mechanisms.

Findings

Pluripotent stem cells can generate various neuronal types for modeling dystonia.

SGCE mutations affecting ε-sarcoglycan are linked to Myoclonus Dystonia.

Stem cell models offer a platform to study dystonia's molecular and cellular mechanisms.

Abstract

Dystonia is a movement disorder with an estimated prevalence of 1.2% and is characterised by involuntary muscle contractions leading to abnormal postures and pain. Only symptomatic treatments are available with no disease-modifying or curative therapy, in large part due to the limited understanding of the underlying pathophysiology. However, the inherited monogenic forms of dystonia provide an opportunity for the development of disease models to examine these mechanisms. Myoclonus Dystonia, caused by SGCE mutations encoding the ε-sarcoglycan protein, represents one of now >50 monogenic forms. Previous research has implicated the involvement of the basal ganglia–cerebello-thalamo-cortical circuit in dystonia pathogenesis, but further work is needed to understand the specific molecular and cellular mechanisms. Pluripotent stem cell technology enables a patient-derived disease modelling platform harbouring disease-causing mutations. In this review, we discuss the current understanding of the aetiology of Myoclonus Dystonia, recent advances in producing distinct neuronal types from pluripotent stem cells, and their application in modelling Myoclonus Dystonia in vitro. Future research employing pluripotent stem cell-derived cellular models is crucial to elucidate how distinct neuronal types may contribute to dystonia and how disruption to neuronal function can give rise to dystonic disorders.

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