A role for cerebellum in the hereditary dystonia DYT1

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Abstract

DYT1 is a debilitating movement disorder caused by loss-of-function mutations in torsinA. How these mutations cause dystonia remains unknown. Mouse models which have embryonically targeted torsinA have failed to recapitulate the dystonia seen in patients, possibly due to differential development compensation between rodents and humans. To address this issue, torsinA was acutely knocked down in select brain regions of adult mice using shRNAs. TorsinA knockdown in the cerebellum, but not in the basal ganglia, was sufficient to induce dystonia. In agreement with a potential developmental compensation for loss of torsinA in rodents, torsinA knockdown in the immature cerebellum failed to produce dystonia. Abnormal motor symptoms in knockdown animals were associated with irregular cerebellar output caused by changes in the intrinsic activity of both Purkinje cells and neurons of the deep cerebellar nuclei. These data identify the cerebellum as the main site of dysfunction in DYT1, and offer new therapeutic targets.

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Rachel Fremont

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.
Ambika Tewari

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 (R01NS079750)

Kamran Khodakhah

National Institute of Neurological Disorders and Stroke (ro1NS050808)

Kamran Khodakhah

National Institute of Neurological Disorders and Stroke (F30NS071665-)

Rachel Fremont

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 of the Albert Einstein College of Medicine. All surgery was performed under anesthesia, and every effort was made to minimize suffering. Protocol Number: 20160805

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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.