Northcott Neuroscience Laboratory

Lab head: A/Prof Marina Kenenrson
Location: ANZAC Research Institue


Finding Genes for Motor and Sensory Neuron Degeneration Using Next Generation Sequencing

Primary supervisor: Marina Kennerson

In recent years significant progress has been made in finding the molecular causes of the premature death of neurons (neurodegeneration). The mechanisms of neurodegeneration can be divided into those that result in death of cell bodies (neuronopathies) and those that result in the ‘dying back’ of the distal neuron (axonal degenerations). Neurons are our longest (up to 1m) and most polarised cells. The unique morphology and the specialised cellular and energy requirements, highlight the inherent vulnerability of neurons to length dependent degeneration.

The Northcott Neuroscience Laboratory at the ANZAC Research Institute has an international reputation for mapping genes for Charcot-Marie-Tooth (CMT) disease, the most common and incurable group of disorders of the peripheral nervous system. Clinical characteristics of CMT include progressive distal limb weakness, muscle atrophy, loss of deep tendon reflexes, and sensory abnormalities. By discovering genes causing CMT we are defining proteins involved with the ‘dying back’ (axonal degeneration) of peripheral nerves. This pathogenic process is common to many neurodegenerative disorders including Parkinson’s disease, Alzheimer’s disease and motor neuron disease.

Gene discovery for CMT has entered an exciting era with the availability of next generation sequencing (NGS) to expedite the gene mutation identification process. This project will contribute to ongoing work in our laboratory to identify gene mutations in families in which the underlying cause of CMT is unknown. Our current strategy is to sequence all known genes by using whole exome sequencing (WES). We are also employing whole genome sequencing (WGS) to assess the role of structural variation in disease pathogenesis. Students will be trained in molecular genetics and bioinformatics skills and gain practical experience using the latest advancements in methods for human disease gene identification and gene functional studies. Specific techniques will include linkage analysis, high resolution melt (HRM) genotyping/mutation screening, bioinformatic analysis of WES/WGS sequence data, and molecular biology/cloning for validation and functional analysis of potential pathogenic DNA variants. These skills will be invaluable for students considering future postgraduate studies or pursuing a career in human neurogenetics/neurosciences.

The Northcott Neuroscience Laboratory is well resourced and currently holds NHMRC. The student will join a dynamic team of postdoctoral fellows, research assistants and fellow students. This project demonstrates the importance of translational medicine and the power of integrating clinical practice with modern genomic technologies. The student will gain insight into how our gene discoveries impact on genomic medicine and lead to positive health outcomes for CMT disease.

Discipline: Pathology
Co-supervisors: Alexander Drew, Gonzalo Perez-Siles, Megan Brewer
Keywords: Bioinformatics, Neuropathy, molecular genetics