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

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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.

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All data generated or analysed during this study are included in the manuscript and supporting files.

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Samantha Washburn

Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United States

Competing interests
The authors declare that no competing interests exist.
Rachel Freemont

Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United States

Competing interests
The authors declare that no competing interests exist.
Maria Camila Moreno-Escobar

Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United States

Competing interests
The authors declare that no competing interests exist.
Chantal Angueyra

Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United States

Competing interests
The authors declare that no competing interests exist.
Kamran Khodakhah

Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United States

For correspondence
k.khodakhah@einstein.yu.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7905-5335

Funding

National Institute of Neurological Disorders and Stroke (NS105470)

Kamran Khodakhah

National Institute of Neurological Disorders and Stroke (NS089716)

Samantha Washburn

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#08-133) of the University of Arizona. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Albert Einstein College of Medicine (Permit Number: 20160805). All surgery was performed under isofulrane anesthesia, and every effort was made to minimize suffering.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.