The Hill lab uses a combination of Biochemistry, Molecular and Cell Biology to investigate these diseases. Prion and Alzheimer’s diseases involve the processing of distinct proteins which when misfolded cause neurodegeneration. We are interested in understanding the molecular mechanisms by which these proteins exert their neurodegenerative properties and in the case of prion proteins, gain their infectious properties.
Prion diseases such as Creutzfeldt‐Jakob disease (CJD) in humans and bovine spongiform encephalopathy (BSE or ‘mad‐cow’ disease) in cattle are invariably fatal neurodegenerative diseases. Prions differ from conventional infectious agents in being highly resistant to treatments that destroy the nucleic acids found in bacteria and viruses. The infectious prion is thought to be an abnormally folded isoform (PrPSc) of a host protein known as the prion protein (PrPC). The conversion of PrPC to PrPSc occurs post‐translationally and involves conformational change from a predominantly α‐helical protein to one rich in β‐sheet structure.
Alzheimer’s disease (AD) is the most common form of dementia in humans, of which the key pathological hallmark is the deposition of the 39‐46 amino acid beta‐amyloid peptide (Aβ) in the brain. Aβ peptides are derived from sequential cleavage of the amyloid precursor protein (APP) by β‐ and γ‐secretases.
The group is investigating the processing and secretion of the prion protein and the APP in association with small membrane vesicles known as exosomes. We have shown that exosomes can transfer infectious prions between different cell types.
Techniques include: We have expertise in various molecular biology techniques (eg, cloning, PCR, real time quantitative PCR, site‐directed mutagenesis, next generation sequencing), cell biology (cell culture, immunofluorescent staining, live cell imaging, RNAi, transfection, lentivirus production, isolation of primary neuronal cells, prion infection assays), protein chemistry (recombinant protein expression and purification, protein gels, western immunoblotting, biophysical techniques), and general biochemical assays. We have expertise in the isolation and deep sequencing of RNA isolated from exosomes using both the SOLiD and Ion Torrent sequencing platforms. We also use cryo-electron microscopy to image exosomes and microvesicles through the Bio21 Institute's Advanced Microscopy Facility.
Professor Andrew Hill is an Principal Research Fellow in the Department of Biochemistry and Molecular Biology at the University of Melbourne. His laboratory studies the molecular and cellular biology of neurodegenerative disorders such as Alzheimer's and prion diseases.
In 1992, he began working on prion diseases in the UK, researched the molecular properties of human and animal prion strains and identified the link between BSE and a new form of prion disease in humans - variant Creutzfeldt-Jakob disease that emerged in 1996. This work led to a number of high profile publications in Nature and Science and to the development of a diagnostic and classification system for human prion diseases.
Andrew first came to Australia in 2000 as a Wellcome Prize Travelling Research Fellow, where he expanded his research interests into other neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Andrew's research team uses in vitro and in vivo models to look at how abnormal prion proteins travel from cell to cell and factors that affect prion infection. This work has extended into identifying similar pathways involved in the processing of the amyloid precursor protein (APP) involved in Alzheimer's disease. His laboratory also works on the basic biology of the prion protein and APP to understand their role in the disease process in more detail, with the goal of translating this into the design of novel therapeutics and diagnostics.
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