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Review
. 2024 Sep 10;13(18):1520.
doi: 10.3390/cells13181520.

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

Zongze Li  1   2 , Laura Abram  1   2 , Kathryn J Peall  1   2
Affiliations
Review

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

Zongze Li et al. Cells. .

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.

Keywords: Myoclonus Dystonia; SGCE; disease modelling; dystonia; epsilon-sarcoglycan; pathogenesis; pluripotent stem cell.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Symptoms and disease progression of Myoclonus Dystonia. (A) Overview of the motor and non-motor features typically observed in Myoclonus dystonia, including dystonia of the neck (cervical dystonia) and upper limbs (writer’s cramp), coupled with a spectrum of psychiatric co-morbidities. (B) Three main patterns of motor symptom evolution (i–iii) in Myoclonus dystonia patients. The red boxes highlight the body regions affected, with the darker colour representing more severe symptoms. Stars label areas where dystonia manifests. Created with BioRender.com.
Figure 2
Figure 2
Hypothesised role of ε-sarcoglycan in the brain dystroglycan complex. αDG: α-dystroglycan; βDG: β-dystroglycan; DGC: dystroglycan complex; Dp71: dystrophin protein 71; ECM: extracellular matrix; and GABAA-R: GABAA receptors. Created with BioRender.com.
Figure 3
Figure 3
Neuronal networks involved in the pathogenesis of dystonia and existing evidence. DA: dopamine; DN: deep cerebellar nuclei; DRD2: dopamine receptor D2; GPe: globus pallidus externus; GPi: globus pallidus internus; LTD: long-term depression; LTP: long-term potentiation; PN: pontine neurons; SNpc: substantia nigra pars compacta; STN: subthalamic nucleus; and TMS: transcranial magnetic stimulation. Created using an icon resource from BioRender.com.
Figure 4
Figure 4
Strategies for generating distinct neuronal subtypes from pluripotent stem cells for dystonia disease modelling. Neurons can be generated from pluripotent stem cells using two strategies: direct reprogramming (blue) and step-wise differentiation (red). CHIR: CHIR99021, WNT signalling activator by inhibiting glycogen synthase kinase-3 beta; CPM: cyclopamine, Sonic hedgehog signalling inhibitor by inhibiting Smoothened protein; FGF2: fibroblast growth factor 2; FGF8a: fibroblast growth factor 8a; PM: purmorphamine, Sonic hedgehog signalling activator by activating Smoothened protein; SHH: Sonic hedgehog, activating SHH signalling; and XAV: XAV939, WNT signalling inhibitor by inhibiting tankyrase 1 and 2. Created with BioRender.com.
Figure 5
Figure 5
Current progress of pluripotent stem cell-derived cellular models for Myoclonus dystonia and future directions. (A,B) Summary of the study design and main findings of two studies of SGCE mutation-positive Myoclonus dystonia (MD) using pluripotent stem cell-derived neurons including patient-derived lines (red) and control lines (blue). (C) Potential future directions of MD research using PSC-derived three-dimensional assembloids and two-dimensional cellular models. AP: action potential; and mEPSC: miniature excitatory post-synaptic current. Created with BioRender.com.
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