# Cerebellar Dysfunction in DYT1

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2021 · $460,304

## Abstract

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 developmental
compensation between rodents and humans. To address this issue, we have developed a new mouse
model where torsinA is acutely knocked down in select brain regions of adult mice using shRNAs. We
have found that torsinA knockdown in the cerebellum, but not in the basal ganglia, is sufficient to induce
dystonia. Abnormal motor symptoms in dystonic 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. This proposal capitalizes on this dystonic model of DYT1 to explore at circuit, neuronal,
and molecular levels how loss of torsinA causes dystonia. The proposal is based on three specific aims. In the first specific aim we will test the hypothesis that in
DYT1 abnormal cerebellar output causes dystonia by altering the activity of the basal ganglia via the
thalamic disynaptic Cb-BG pathway that we have characterized. Specific Aim 2 will test the hypothesis
that selective knock down of torsinA in cerebellar Purkinje cells and/or DCN neurons causes cerebellar
dysfunction and dystonia. And lastly the third specific Aim tests the hypothesis that knock down of
torsinA alters the intrinsic pacemaking of Purkinje cells and DCN neurons by altering the expression or
function of select conductances. Successful accomplishment of the aims set will significantly advance our understanding of DYT1
dystonia, and may provide valuable potential therapeutic targets for its treatment.

## Key facts

- **NIH application ID:** 10072088
- **Project number:** 5R01NS105470-05
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Kamran Khodakhah
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $460,304
- **Award type:** 5
- **Project period:** 2017-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072088

## Citation

> US National Institutes of Health, RePORTER application 10072088, Cerebellar Dysfunction in DYT1 (5R01NS105470-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10072088. Licensed CC0.

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