Motor neuron disease (also known as amyotrophic lateral sclerosis, ALS) is a devastating illness involving loss of motor neurons in the spinal cord. The disease normally leads to paralysis and death after 2-5 years, and there is no effective long-term treatment or cure. The cause of ALS is not known. Most cases are sporadic with unknown cause but there are also a small number caused by genetic mutation. During the disease course, protein accumulation occurs in affected neurons and inflammation also occurs by surrounding glia. In addition, accumulation of oxidative damage is a major marker of pathology in the spinal cord. Oxidative damage is caused by reactive oxygen species (ROS) that target proteins, lipids and nucleic acids. The reason for this accumulation of ROS and subsequent oxidative damage is not known.
Some studies have shown that there are changes to a master regulator of antioxidant function in ALS patients. This master regulator is a transcription factor called Nrf2. It controls the gene expression of more than 200 genes involved in regulating oxidative stress and inflammation. Its impairment in ALS may be leading to accumulation of oxidative damage to neurons. Our recent studies have identified an important link between Nrf2 and an RNA-binding protein, hnRNP K. In some cases of ALS, altered hnRNP K regulation is stopping Nrf2 from functioning correctly.
In this project, we are seeking to determine if changes to Nrf2 function occur in ALS patients with a broad range of genetic mutations, or in those with sporadic disease, and whether hnRNP K is involved in Nrf2 dysfunction. We will also determine whether inducers of Nrf2 activation are able to up-regulate Nrf2 function as a potential therapeutic approach. To achieve this, we are examining Nrf2 in inducible pluripotent stem cells (iPSC) taken from patients with ALS and from cells and tissues taken from animal models of ALS. These cells/tissues are examined for Nrf2 function and activity of downstream antioxidant targets to understand the pathological changes that drive oxidative stress and neuronal degeneration in ALS. This project will involve cell culture of neural stem cells, microscopy, qRT-PCR and western blotting.
- PhD project but may also be considered for an Honours project.