Lawson Laboratory

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

• Collins SJ, Lewis V, Brazier MW, Hill AF, Lawson VA, Klug GM, Masters CL. Extended period of asymptomatic prion disease after low dose inoculation: Assessment of detection methods and implications for infection control. Neurobiol Dis (In press)
• Vella LJ, Sharples RA, Lawson VA, Collins SJ, Masters CL, Cappai R, Hill AF. Proteomic investigation into the propagation and spread of infectious prions in non-neuronal cells. FEBS Journal, 272(s1);123-4, 2005.
• Lawson VA , Collins SJ , Masters CL , Hill AF . Prion protein glycosylation. J Neurochem. 2005 May;93(4):793-801.
• Collins SJ , Lawson VA , Masters CL . Transmissible spongiform encephalopathies. Lancet. 2004 Jan 3;363(9402):51-61.
• Lawson VA , Priola SA , Meade-White K , Lawson M , Chesebro B . Flexible N-terminal region of prion protein influences conformation of protease-resistant prion protein isoforms associated with cross-species scrapie infection in vivo and in vitro. J Biol Chem. 2004 Apr 2;279(14):13689-95.