A neurodevelopmental origin of dystonia

Maintaining control over bodily movements is critical for our wellbeing. Many neurological diseases, however, result in a loss of such control, diminishing quality of life. Here, I focus on one such disease that is prevalent yet poorly understood: dystonia.

Dystonia is characterised by involuntary muscle contractions that result in twisted, contorted postures. Over 90,000 patients in the UK alone suffer from this disease. Dystonic movements are frequently painful and may begin at an early age - in some cases, just weeks after birth. Furthermore, dystonia is often associated with additional disease symptoms, including other movement disorders such as Parkinsonism, ataxia, dyskinesia, and myoclonus; and non-movement-related disorders such as epilepsy, autism, intellectual disability and developmental delay. Unfortunately, therapeutic options to treat dystonia are limited. This is primarily due to a lack of understanding regarding the fundamental molecular and cellular basis of involuntary movements in this disorder.

In this Fellowship application, I describe a series of approaches to uncover such mechanisms using the fruit fly, Drosophila melanogaster - a model organism with unparalleled rapidity of use and a hugely powerful toolkit that readily enables manipulations of both genes and neural circuits. I introduce a novel Drosophila model of dystonia; demonstrate that this model exhibits dystonia-like alterations in movement and the activity of neural circuits that influence movement; and show how this model can be used to uncover cellular pathways that cause dystonia. I propose to confirm the broader relevance of our findings by generating a new array of Drosophila dystonia models, and to utilise these models to identify novel drug treatments.

Furthermore, I have built a unique network of national and international collaborators specialising in the study of dystonia genetics, neurophysiology, and mouse models of the disease. This network will allow me to greatly increase translational impact by using our results to guide studies in human and mammalian systems, to confirm the validity of potential drug treatments in mammalian dystonia models.
Implementation of my experimental strategy promises to greatly enhance our understanding of how dystonic movement arise, and uncover novel therapeutic methods to treat this debilitating disorder. Achieving these goals may also shed light on the large number of neurological diseases that are frequently co-morbid with dystonia.

Here I propose a series of approaches to study the mechanistic basis of a prevalent yet poorly understood movement disorder: dystonia.
Dystonia is characterised by involuntary muscle contractions, leading to twisted, contorted postures. It is the third most common movement disorder, affecting over 90,000 patients in the UK alone. Furthermore, dystonia is often co-morbid with a wide array of neurological syndromes, including Parkinsonism, ataxia, dyskinesia, tremor, autism, epilepsy, and intellectual disability. However, the molecular basis of dystonia has remained mysterious. In particular, whether mutations linked to inherited dystonia impact the development of movement-controlling neural circuits has yet to be resolved.

To define the molecular basis of dystonia, my lab has generated a Drosophila model of an inherited dystonia linked to a mutation in the hSlo1 BK channel. This model exhibits organismal and circuit-level phenotypes similar to those observed in dystonia patients. Using genetic techniques unique to Drosophila, I unambiguously show that mutant BK channels act in cholinergic neurons and during a critical neurodevelopmental window to perturb movement; and alter the developmental of premotor circuits. I aim to uncover molecular mechanisms underlying these effects, and to confirm the broader relevance of these findings by generating an array of additional Drosophila models of dystonia. I further propose to take advantage of the unique opportunities presented by Drosophila models by performing a screen for novel drugs to treat dystonic movements.

My proposal will enhance our fundamental knowledge relating not only to dystonia but also a range of disorders that frequently occur in concert with it. Thus, my proposal will have a broad, translationally significant impact and will significantly enhance my career development by allowing me to realise my aim of becoming an international leader in the field of neurological disease.