Lawson Laboratory
| Contact: | Victoria Lawson |
|---|---|
| Phone: | +61 3 8344 1944 |
| Fax: | +61 3 8344 4004 |
| Email: | v.lawson@unimelb.edu.au |
The Lawson laboratory studies how host derived factors contribute to the formation of the protease resistant form of the prion protein and the role of this misfolded protein in the transmission and pathogenesis of prion diseases.
Key research areas are
Prion diseases are transmissible, neurodegenerative disorders affecting both humans and animals. The most common form in humans is sporadic Creutzfeldt-Jakob disease (spCJD), although acquired (variant CJD) and inherited (familial CJD) forms also exist. The 'prion' hypothesis has been used to explain the transmission of prion diseases in the absence of conventional infectious agents, such as a virus or bacteria. This hypothesis proposes that an abnormal isomer (PrP Sc ) of the host-encoded cellular prion protein (PrP C ), is the sole or principal component of the infectious agent or 'prion'. Cell-free assays of prion propagation have been used to demonstrate the ability of a PrP Sc template to generate de novo a protease-resistant form of PrP from a source of PrP C . A cell-free Conversion Activity Assay is used in the Lawson Laboratory to investigate how host derived factors contribute to the propagation of prions.
The role of glycosaminoglycan in the propagation of prions.
Glycosaminoglycans (GAGs) are complex, negatively charged molecules found on cell surfaces and in extracellular matrices. GAGs are associated with many neurodegenerative protein misfolding diseases and there is strong experimental support for an active role for GAGs in prion diseases. Current studies are aimed at understanding how GAGs facilitate the formation of the protease resistant form of the prion protein and how this relates to disease transmission and pathogenesis.
The molecular basis of the propagation of molecular strain types of prions.
Prion strains have been characterized on the basis of incubation time, neuropathology and clinical phenotype. Prion strains can also been characterized at a molecular level on the basis of the electrophoertic mobility of PrP Sc after protease digestion, glycosylation pattern and association with polymorphisms in the prion protein gene. Current studies are aimed at understanding how host-derived factors influence the propagation of molecular strain types.
Objectives
To use an integrated system of biochemical, molecular, cellular and structural biology methods in an effort to understand key events in prion disease transmission and pathogenesis with a view to identifying crucial early diagnostic and therapeutic approaches to prion diseases.
Recent Achievements
Identification of peripheral tissues that support the formation of the protease resistant form of the prion protein.
Techniques
- Conversion Activity Assay
- Western blotting
- Cell culture
- Molecular Biology
Collaborations
Departmental:
A. Hill, S. Collins, K. Barnham
External:
D. Hoke ( Monash University )
Funding
- NHMRC
- Melbourne Research Grants Scheme
- Industry funding
Recent Publications
- Lawson, V. A., Priola, S. A., Wehrly, K., and Chesebro, B. (2001) N-terminal truncation of prion protein affects both formation and conformation of abnormal protease-resistant prion protein generated in vitro. J Biol Chem 276, 35265-35271
- Priola, S. A., and Lawson, V. A. (2001) Glycosylation influences cross-species formation of protease-resistant prion protein. EMBO J 20, 6692-6699
- Collins, S. J., Lawson, V. A., and Masters, C. L. (2004) Transmissible spongiform encephalopathies. Lancet 363, 51-61
- Collins, S. J., Lewis, V., Brazier, M. W., Hill, A. F., Lawson, V. A., Klug, G. M., and Masters, C. L. (2005) Extended period of asymptomatic prion disease after low dose inoculation: assessment of detection methods and implications for infection control. Neurobiol Dis 20, 336-346
- Lawson, V. A., Collins, S. J., Masters, C. L., and Hill, A. F. (2005) Prion protein glycosylation. J Neurochem 93, 793-801
- Brazier, M. W., Lewis, V., Ciccotosto, G. D., Klug, G. M., Lawson, V. A., Cappai, R., Ironside, J. W., Masters, C. L., Hill, A. F., White, A. R., and Collins, S. (2006) Correlative studies support lipid peroxidation is linked to PrP(res) propagation as an early primary pathogenic event in prion disease. Brain Res Bull 68, 346-354
- Lawson, V. A., Stewart, J. D., and Masters, C. L. (2007) Enzymatic detergent treatment protocol that reduces protease-resistant prion protein load and infectivity from surgical-steel monofilaments contaminated with a human-derived prion strain. J Gen Virol 88, 2905-2914
- Vella, L. J., Sharples, R. A., Lawson, V. A., Masters, C. L., Cappai, R., and Hill, A. F. (2007) Packaging of prions into exosomes is associated with a novel pathway of PrP processing. J Pathol 211, 582-590
- Albanese, V., Lawson, V. A., Hill, A. F., Cappai, R., Di Guardo, G., Staikopoulos, V., Thacker, M., Furness, J. B., and Chiocchetti, R. (2008) Evidence for prion protein expression in enteroglial cells of the myenteric plexus of mouse intestine. Auton Neurosci 140, 17-23
- Lawson, V. A. (2008) Quantitative bioassay of surface-bound prion infectivity. Methods Mol Biol 459, 265-273
- Lawson, V. A. (2008) Understanding the nature of prion diseases using cell-free assays. Methods Mol Biol 459, 97-103
- Lawson, V. A., Vella, L. J., Stewart, J. D., Sharples, R. A., Klemm, H., Machalek, D. M., Masters, C. L., Cappai, R., Collins, S. J., and Hill, A. F. (2008) Mouse-adapted sporadic human Creutzfeldt-Jakob disease prions propagate in cell culture. Int J Biochem Cell Biol 40, 2793-2801
- Haigh, C. L., Drew, S. C., Boland, M. P., Masters, C. L., Barnham, K. J., Lawson, V. A., and Collins, S. J. (2009) Dominant roles of the polybasic proline motif and copper in the PrP23-89-mediated stress protection response. J Cell Sci 122, 1518-1528