Lipid homeostasis disruption in DYT-TOR1A dystonia
Year of award: 2024
Grantholders
Dr Abigail Wilson
University College London, United Kingdom
Project summary
Dystonia is the third most common movement disorder characterised by painful involuntary muscle contractions that disrupt coordinated locomotion. However, the neuronal dysfunction that drives the movement disorder in dystonia is poorly understood, resulting in a severe lack of therapeutic targets. The most common form of inherited dystonia is DYT-TOR1A caused by mutations to Torsin (TorsinA/Tor1a), a AAA+ ATPase that localises to the nuclear envelope and has important roles in the modulation of lipids. Torsin knock-out causes locomotor deficits and disruption to lipid homeostasis. However, it is not known if acutely restoring the disrupted lipidome can ameliorate dystonia-related locomotor dysfunction. This proposal aims to use a Torsin knock-out Drosophila model to test this. I will characterise important pathological features of human dystonia in the Drosophila model including defects in limb kinematics, antagonistic co-contractions, and nuclear envelope morphology defects. Next, I will use a high-throughput modality to identify drugs that can acutely modify lipid homeostasis and rescue dystonia-related locomotor dysfunction. Finally, I aim to define if there is a neuron-specific basis for acute lipidome homeostasis rescue in Torsin knock-out Drosophila. This research promises new opportunities for understanding dystonia pathologies and aims to identify novel targets to improve therapeutic options for dystonia patients.