Andy Hill
Prion diseases
Prion diseases are a unique group of invariably fatal neurodegenerative diseases affecting humans and animals. They include Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep, and bovine spongiform encephalopathy (BSE or mad-cow disease) in cattle. These diseases can be inherited through mutations in the prion protein gene. They are transmissible to the same species by inoculation with infected tissues or ingestion of infected materials. They may also occur spontaneously. The occurrence of variant CJD (vCJD) in humans and the experimental confirmation that it is caused by the same prion strain as BSE has highlighted the need for study into the pathogenesis of these diseases. Much evidence suggests that the principal or sole component of the infectious agent causing these diseases is an abnormal isoform of the host-encoded product of the prion gene. The abnormal form of the prion protein (called PrPSc) is derived from the normal form post-translationally, presumably via a conformational change in the structure of the protein. Another area of investigation in collaboration with Danny Hatter’s lab is how the aberrant infectious conformation of the prion protein moves within and between cells.
Protein-only model of prion propagation: The normal form of prion protein, PrPC (open circles) interacts with the disease-associated form, PrPSc (closed objects), resulting in conversion of PrPC to PrPSc. Prions can also be introduced into the organism by inoculation or spontaneous conversion of PrPC containing a mutation in the PrP open reading frame.
Prion strains and species barriers
ike other infectious diseases caused by conventional infectious agents, several strains of prions exist which result in different disease phenotypes. Different prion strains can target different parts of the brain, resulting in defined patterns of neurodegeneration. We are interested in examining how different strains of prions can exist given there is no known genetic component to an infectious prion. As the amino acid sequence of the prion protein is identical in different prion strains from the same species, it is considered that the conformation and post-translational modifications of PrPSc carry the information which encipher these strains. Additionally, species-specific differences in the amino acid sequence of PrP contribute to the species barrier which appears to prevent prions from one species from infecting another species
Pathogenesis of prion diseases
The mechanism of neurotoxicity and exact structure of the neurotoxic prion molecule have not been defined. There are instances where animals infected with prions can harbour high levels of infectious prions in their brains while showing no signs of neurodegeneration. This suggests that other cellular factors or events may be critical for the development of prion disease. Understanding the role of such events in the pathogenesis of these diseases and defining the neurotoxic prion molecule are crucial to early diagnostic and therapeutic approaches. Using in vitro and in vivo approaches in collaboration with Dr Steve Collins, Dr Roberto Cappai and Professor Colin Masters in the Department of Pathology, University of Melbourne, we are interested in examining the pathogenesis of prion disease in more detail, as well as dissecting the pathways involved in the conversion of PrPC to PrPSc. Understanding of the pathways involved in the pathogenesis of prion diseases may be relevant to other neurodegenerative disorders, such as Alzheimer's diseases.
Lab personnel
HeadAssociate Professor Andy HillResearch staffDr Shayne Bellingham (Peters Bequest Fellow) Graduate studentsBradley Coleman Honours studentsMaya Olshina |