# Determining the Pathogenesis of DYT1 Dystonia in Reprogrammed Human Neurons

> **NIH NIH R21** · UNIVERSITY OF LOUISIANA AT LAFAYETTE · 2020 · $197,837

## Abstract

TITLE
Determining the pathogenesis of DYT1 dystonia in reprogrammed human neurons
ABSTRACT
The overall goal of this project is to determine the pathogenesis of dystonia via reprogramming human neurons
from patient fibroblasts. Dystonia is the third most common movement disorder characterized by sustained or
intermittent muscle contractions causing abnormal movements, postures, or both. There is no effective treatment
to cure this disease due to largely unknown the pathological mechanisms.
The childhood onset DYT1 dystonia represents the most frequent and severe form of dystonia, providing an
excellent example to understand the pathogenesis of dystonia disease. The typical DYT1 dystonia is caused by
a heterozygous GAG deletion in TOR1A gene. Very interestingly, mice with the identical torsin A mutation as a
heterozygote failed to show any pathological phenotypes, suggesting that the substantial differences of
pathophysiological mechanisms exist between DYT1 mouse models and human patients. In torsin A knockout
mice, one pathological hallmark is the abnormal nuclear envelope (NE) morphology in multiple areas of central
nervous system (CNS). The large ventral horn neurons in the spinal cord were particularly severe, suggesting
that lower motor neurons (MNs) could be the most severely affected neuron type in DYT1 dystonia. Whether the
abnormalities occurred in DYT1 mice also occur in human patients? What are the effects of such abnormalities
on neuron functions and what are underlying molecular mechanisms? These pertinent questions remained
unanswered because the limited access to patient neurons and the lack of in vitro human neuron systems that
greatly impede the progress of dystonia research.
Excitingly, using lentiviral delivery of transcription factors, we have successfully generated human neurons from
fibroblasts of DYT1 patients and healthy controls via two strategies: (1) direct conversion and (2) induced
pluripotent stem cells (iPSCs)-based reprogramming and differentiation. Using these patient-specific neurons,
we will perform two specific aims: (1) to systematically examine the NE morphology and the nucleocytoplasmic
transport (NCT) of mRNA and protein cargos, and (2) to identify dysregulated factors in human DYT1 neurons,
including mis-localized mRNAs. The contributions of these identified factors to the disease will be focused in our
follow-up studies. Expected results emanating from this study will provide novel insights into dystonia pathology
and potentially lead to molecular targets for therapeutic interventions.

## Key facts

- **NIH application ID:** 9958481
- **Project number:** 1R21NS112910-01A1
- **Recipient organization:** UNIVERSITY OF LOUISIANA AT LAFAYETTE
- **Principal Investigator:** Baojin Ding
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $197,837
- **Award type:** 1
- **Project period:** 2020-04-01 → 2022-01-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9958481

## Citation

> US National Institutes of Health, RePORTER application 9958481, Determining the Pathogenesis of DYT1 Dystonia in Reprogrammed Human Neurons (1R21NS112910-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/9958481. Licensed CC0.

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