# Non-Invasive Markers of Neurodegeneration in Movement Disorders

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2021 · $410,658

## Abstract

SUMMARY
Dystonia is a neurological movement disorder characterized by sustained or intermittent muscle contractions,
which result in abnormal movements and postures. DYT1 dystonia is an autosomal dominant primary dystonia.
Affected individuals are disabled and many times confined to a wheelchair. DYT1 dystonia results primarily from
an in-frame GAG deletion in exon 5 of DYT1/TOR1A, resulting in a loss of glutamic acid at the C-terminal region
of torsinA (torsinAΔE). Although primary dystonia is classically considered a disorder of basal ganglia origin, it is
becoming clear that brain circuits that involve both the basal ganglia and cerebellum are fundamental in
contributing to the symptoms of dystonia. At the same time, we know very little about how torsinA function in
specific cell types and across specific brain regions will unleash motor deficits and pathophysiological signatures
of dystonia. To address this question, we will leverage three key innovations from our experimental team that
position our group to accomplish this goal. First, we have developed a molecular genetics approach that can
selectively target the function of specific cell types, such that some cells remain deficient in torsinA while others
function normally. We will use this approach to specifically target cell types including: 1) medium spiny neurons,
cholinergic neurons, dopamine receptor 2 neurons, and dopaminergic neurons within basal ganglia, 2)
glutaminergic neurons within cortex, and 3) Purkinje neurons within cerebellum. Second, we will leverage our
experience in behavioral phenotyping and electromyography to characterize dystonia-related deficits in the
mouse models. We will quantify muscle co-contraction using electromyography, hindlimb clasping, and other
tests of dystonia-related motor deficits. Third, a key innovation will be to use advanced, high-field brain imaging
at 11.1 Tesla using in vivo multi-shell diffusion imaging to assess structural degeneration, resting state functional
magnetic resonance imaging (fMRI) to assess functional connectivity, and sensory-evoked fMRI to assess the
integrity of sensory neurons across the brain. In Aim 1, we will explore cell-specific effects on Tor1a (Dyt1) ΔGAG
heterozygous knock-in (KI) mice. In Aim 2 we will explore cell-specific effects in a mouse model characterized
by Cre-recombinase expression and conditional knock-out (cKO) of torsinA. The use of behavioral phenotypes
and non-invasive neuroimaging markers will provide fundamental understanding of the cell-specific mechanisms
related to dystonia, provide translational read-outs for future preclinical therapeutic studies in mouse, and the
neuroimaging markers used here will have direct translation to humans.

## Key facts

- **NIH application ID:** 10242723
- **Project number:** 5R01NS075012-09
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** YUQING LI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $410,658
- **Award type:** 5
- **Project period:** 2012-09-24 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242723

## Citation

> US National Institutes of Health, RePORTER application 10242723, Non-Invasive Markers of Neurodegeneration in Movement Disorders (5R01NS075012-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242723. Licensed CC0.

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