Acute cerebellar knockdown of Sgce reproduces salient features of myoclonus-dystonia (DYT11) in mice.

Samantha Washburn,Kamran Khodakhah,Rachel Fremont,Maria Camila Moreno-Escobar,Chantal Angueyra

doi:10.7554/elife.52101

Abstract

Myoclonus dystonia (DYT11) is a movement disorder caused by loss-of-function mutations in SGCE and characterized by involuntary jerking and dystonia that frequently improve after drinking alcohol. Existing transgenic mouse models of DYT11 exhibit only mild motor symptoms, possibly due to rodent-specific developmental compensation mechanisms, which have limited the study of neural mechanisms underlying DYT11. To circumvent potential compensation, we used short hairpin RNA (shRNA) to acutely knock down Sgce in the adult mouse and found that this approach produced dystonia and repetitive, myoclonic-like, jerking movements in mice that improved after administration of ethanol. Acute knockdown of Sgce in the cerebellum, but not the basal ganglia, produced motor symptoms, likely due to aberrant cerebellar activity. The acute knockdown model described here reproduces the salient features of DYT11 and provides a platform to study the mechanisms underlying symptoms of the disorder, and to explore potential therapeutic options.

Highlights

Dystonia is a hyperkinetic movement disorder characterized by involuntary co-contraction of agonist and antagonist muscles resulting in abnormal, repetitive movements and pulled or twisted postures that cause varying degrees of disability and pain (Albanese et al, 2013)
We hypothesized that developmental compensation for genetic knockout of Sgce could account for the mild motor symptoms observed in previous mouse models of DYT11
The primary goal of this study was to test the hypothesis that acute knockdown of Sgce, the mouse homolog of the gene responsible for DYT11 in humans, in adult mice would more accurately model DYT11 by circumventing compensation that might occur in transgenic mouse models where the protein is absent throughout the development of the brain

Summary

Introduction

Dystonia is a hyperkinetic movement disorder characterized by involuntary co-contraction of agonist and antagonist muscles resulting in abnormal, repetitive movements and pulled or twisted postures that cause varying degrees of disability and pain (Albanese et al, 2013). The prevalence of dystonia in the general population has been notoriously difficult to determine precisely, due to different methodologies for case classification, but a recent meta-analysis estimated that primary dystonia occurs at a rate of approximately 16 per 100,000 (Steeves et al, 2012). This is likely an underestimate, as cases frequently go undiagnosed and dystonia can be a secondary symptom in other motor disorders. Myoclonus-dystonia (DYT11) is a dominantly inherited form of dystonia caused by loss-of-function mutations in the SGCE gene, which encodes the protein epsilon sarcoglycan (ε-SG) (Zimprich et al, 2001). In DNA and RNA samples from human blood SGCE is maternally imprinted, but the imprinting pattern in the brain is unknown (Grabowski et al, 2003)

Objectives

Results

Conclusion