# TorsinA mediated regulation of Cdc42 signaling and DYT1 dystonia

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2021 · $314,000

## Abstract

PROJECT SUMMARY/ABSTRACT
DYT1 dystonia is a devastating neurological movement disorder characterized by uncontrolled muscle
contractions that result in abnormal, involuntary postures. DYT1 dystonia is caused by a deletion (Δgag; ΔE) in
the Tor1A gene encoding the luminal ATPases associated with various cellular activities (AAA+) protein
torsinA. How the ΔE mutation causes DYT1 dystonia remains unclear because the basic cellular function
performed by torsinA is unknown. This proposal seeks to close these critical gaps in knowledge, which will
enable the rational design of urgently needed targeted therapies. Our recent work suggests that torsinA is i)
required for the transduction of mechanical signals from the cytoskeleton into the nucleoplasm via the nuclear
envelope spanning linker of nucleoskeleton and cytoskeleton (LINC) complex; ii) the activation of signaling
mediated by the Rho GTPase Cdc42; iii) as well as proper axon outgrowth and growth cone morphology.
Importantly, axonal tract disruptions that correlate with clinical severity are observed in the brains of DYT1
dystonia patients and the both the LINC complex and Cdc42 mediate axon elongation and guidance. Thus, we
hypothesize that defective torsinA-dependent mechano-chemical signal transduction contributes to DYT1
dystonia pathogenesis. We will test this hypothesis in cultured mammalian cells and the African clawed frog
Xenopus laevis using an array of established and novel biochemical, biophysical, fluorescent Rho GTPase
biosensors, quantitative imaging and proteomics, as well as synthetic biological approaches. In this proposal,
we will define how torsinA and its co-activator, the inner nuclear membrane protein LAP1, regulate the
assembly of functional LINC complexes in cultured mammalian cells (Aim 1). We will determine how torsinA
and its other co-activator, the outer nuclear membrane protein LULL1, control the activation of Cdc42 in
cultured mammalian cells (Aim 2). Finally, we will test the role of torsinA-dependent mechano-chemical signal
transduction during axon outgrowth in cultured X. laevis neurons and in the brains of living embryos (Aim 3).
The results of these Aims will provide invaluable mechanistic insights into the emerging role of
the nuclear envelope as a signaling node in development and disease. Furthermore, they will lay the
foundation for the future development of novel therapeutic strategies for the treatment of other forms of
dystonia, dystonia plus syndromes in which dystonia can occur in conjunction with another neurological
disorder such as Huntington's and Parkinson's diseases, as well as other neurologic and neuropsychiatric
diseases caused by mutations in LINC complex proteins including autism, ataxia, bipolar disorder, dementia,
and schizophrenia.

## Key facts

- **NIH application ID:** 10264131
- **Project number:** 5R01GM129374-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** George William Gant Luxton
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $314,000
- **Award type:** 5
- **Project period:** 2018-09-17 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10264131

## Citation

> US National Institutes of Health, RePORTER application 10264131, TorsinA mediated regulation of Cdc42 signaling and DYT1 dystonia (5R01GM129374-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10264131. Licensed CC0.

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