Research Fellows Directory
Dr Natalia Gromak PhD
University of Oxford
Ataxia oculomotor apraxia type 2 (AOA2) and amyotrophic lateral sclerosis type 4 (ALS4) are highly disabling inherited motor neuron disorders, characterized by degeneration in the brain and spinal cord, causing progressive muscle weakness and finally atrophy. These disorders arise due to mutations in a protein called senataxin. Since the discovery of AOA2/ALS4 mutations in 2004, little progress has been made to characterize the function of senataxin protein or molecular mechanisms of AOA2/ALS4 pathology.
In this research project we will study the function of senataxin, by performing experiments in human cells which have been depleted of senataxin protein or derived from patients’ tissues. We propose that AOA2/ALS4 diseases arise due to defects in senataxin function, which acts to unravel binding of the newly synthesised messenger RNA to DNA during transcription. If such faulty RNA/DNA molecules accumulate, they can become detrimental to the cell function, causing pathologies. Analysing the entire genetic makeup of the cells from AOA2/ALS4 patients, we will characterise how these RNA/DNA molecules contribute to the neurodegeneration symptoms. We will also identify specific defects in transcription and splicing arising from senataxin mutations. Finally we will uncover novel RNAs and proteins that interact with senataxin and study their function in gene expression and AOA2/ALS4 pathology
The outcome of this research project will be beneficial to all AOA2/ALS4 patients affected by mutations in senataxin and clinicians, directly involved in treating these patients. Our work will make a major contribution to understanding of AOA2/ALS4 disorders, making the strategy for their diagnosis more efficient. In the long term, development of novel pharmacological and RNA-based therapies, improving the health and quality of life of AOA2/ALS4 and other neurodegenerative patients with defects of RNA processing, are a likely prospect from our research.
Interests and expertise (Subject groups)