# Pathophysiology of DYT1 dystonia: Targeted Mouse Models

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2024 · $354,228

## Abstract

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing
abnormal, often repetitive, movements or postures. DYT1 early-onset generalized dystonia is the most
common type among the genetic dystonias. Most of the individuals affected by DYT1 dystonia share a
trinucleotide deletion (ΔGAG) located in exon 5 of DYT1 or TOR1A gene, leading to a loss of a glutamate
amino acid residue for torsinA (torsinA∆E). The symptoms start from limbs and then become generalized.
Affected individuals could be seriously disabled and need to use a wheelchair. Conditional knockout of torsinA
in mice points to the involvement of multiple brain regions and cell types in the pathogenesis of DYT1 dystonia.
These and other pathophysiological studies of DYT1 and other dystonias so far support a circuit or network
model of dystonia pathogenesis. However, which brain region and neuronal types play a critical role in
pathogenesis is unclear. Alterations of both the striatal dopaminergic and cholinergic systems appear to play a
critical role in the pathophysiology of DYT1 dystonia. Dopaminergic modulation of striatal cholinergic
interneurons (ChIs) is altered in multiple dystonia models that include DYT1 dystonia. Whether torsinA∆E in
striatal ChIs has the cell-autonomous effect on striatal cholinergic dysfunction is not known. Preliminary studies
of conditional knockin (KI) mouse models of DYT1 dystonia revealed dopaminergic and striatal medium spiny
neurons (MSNs), but not ChIs, play a vital role in the pathogenesis of DYT1 dystonia. However, how torsinA∆E
in MSNs and dopaminergic neurons lead to dystonia is unknown. These unknowns impede the progress in
developing effective treatment for DYT1 patients, especially gene-based targeted therapy with CRISPR,
antisense oligonucleotides, or small hairpin RNA. The broad, long-term objective of our research is 1) to
determine the functional role of torsinA and the mechanism by which torsinA∆E leads to early-onset dystonia, 2)
to develop novel and effective therapeutic treatment. The specific goal of this application is to generate and
analyze five lines of conditional KI mice to understand the role of the striatal dopaminergic system and MSNs
in the pathogenesis of DYT1 dystonia. We hypothesize that torsinA∆E in dopaminergic neurons and MSNs, but
not ChIs, leads to abnormal firing of these neurons, decreased D1R and D2R in MSNs, altered striatal
dopamine release, impaired corticostriatal LTD, altered direct and indirect pathways, and ultimately sustained
muscle contractions and co-contractions that are characteristic of dystonia. Aim 1 will generate conditional
MSN KI mice restricted to direct pathway, indirect pathway, or both and determine their phenotype. In Aim 2,
we will introduce torsinA∆E specifically in dopaminergic neurons or ChIs and determine their dystonia-related
phenotypes. The successful completion of the proposed research will significantly increase our understanding
of the ...

## Key facts

- **NIH application ID:** 10908596
- **Project number:** 5R01NS129873-03
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** YUQING LI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $354,228
- **Award type:** 5
- **Project period:** 2022-09-28 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10908596

## Citation

> US National Institutes of Health, RePORTER application 10908596, Pathophysiology of DYT1 dystonia: Targeted Mouse Models (5R01NS129873-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10908596. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*