Structural Neurobiology

Project Details

Mental illness encompasses a multitude of devastating conditions that present a major burden to the Australian economy. These conditions are often chronic and debilitating, posing the highest health, economic and social capital attrition burden to Australia of any disease group. We are pursuing a number of projects with aim of understanding how key proteins function in the brain with the ultimate aim of discovering new drugs to treat mental illness. Examples include:

Amyloid Precursor Protein (with Professor Colin Masters and Associate Professor Kevin Barnham, Florey Institute)

Alzheimer's disease is the most prevalent neurodegenerative disease in humans and is the fourth leading cause of death in the developed world. The disease is characterised by the presence of amyloid plaques that principally derive from amyloid precursor protein (APP). The long term aim of this project is to determine the complete structure of APP in order to understand its normal physiological function and as a basis for structure-based drug design of anti-Alzheimer's drugs. We are solving the structure of APP by a divide-and-conquer approach: solving the structures of small, overlapping fragments with the eventual aim of piecing the molecule together. To date we have determined the structures of three regions of APP: the growth factor domain, the copper-binding domain and the Abeta peptide bound to a range of clinically relevant antibodies.

IRAP (with Dr Siew Yeen Chai, Monash University)

Central administration of the hexapeptide angiotensin IV markedly enhances memory and learning in rodents. This effect is mediated by binding to a specific, high-affinity site in the brain which our collaborators identified to be the transmembrane enzyme, insulin-regulated aminopeptidase (IRAP). The peptide binds with high affinity to the catalytic domain of IRAP inhibiting its enzymatic activity. Using a molecular model of the catalytic domain, we have screened compound databases and have identified compounds that inhibit IRAP and reverse memory deficits in animals. To date, there is no proven effective treatment for cognitive impairment. Since the causes of cognitive impairment range from birth defects (Down's syndrome, mental retardation, cerebral palsy), recreational drug abuse, opportunistic infections to neurological conditions (stroke, brain trauma, neurodegeneration such as Alzheimer's disease), prevention therapies are not effective alternatives. The IRAP inhibitors may lead to the development of new classes of cognitive enhancers.