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Mechanisms of Prion Diseases
PROFESSOR SIMON HAWKE
Medical Foundation Fellow 2005-2009, Jessie Alberti Program Grant
P
rofessor Simon Hawke took up the Jessie Alberti Program Grant
in February 2005 to continue his work on the transmissible
spongiform encephalopathies, a group of disorders which includes
Creutzfeldt-Jakob disease (CJD) and animal diseases such as bovine
spongiform encephalopathy (BSE or mad cow disease).
Work with prions, the infectious agents thought to cause prion
diseases, requires a tightly controlled environment and stringent
practices designed to avoid environmental contamination. Purpose-
built containment laboratories have been designed for Professor
Hawke and his team. The laboratories are under construction in the
Brain and Mind Research Institute of the University of Sydney and
are due for completion in mid 2006. Mice deficient in the prion
protein gene have been imported from Europe for use in raising
new anti-prion antibodies and work using the infectious agent will
soon commence.
While waiting for the BMRI laboratory to be completed, two projects
have been commenced.
1. Prion-induced neurodegeneration. Subsequent to the
discovery by Professor Hawke and his team at Imperial College,
London, that prion replication can be suppressed by the passive
transfer of anti-prion antibodies (Nature 2003), Solforosi and
colleagues at the University of California, San Francisco, showed
that anti-prion antibodies injected into the mouse hippocampus
induced neurodegeneration by cross-linking normal cellular prion
protein (Science 2004). This later work raised concerns about
translating Professor Hawke's mouse experiments into therapy
for patients with CJD. Understanding how antibodies specific for
prion protein induce the degeneration of neurons is of paramount
importance. Professor Hawke and colleagues, also supported by
the Jessie Alberti Program Grant, have now developed a neuronal
cell culture model in order to identify the cellular pathways causing
this antibody-induced neurodegeneration. This work may also
have important ramifications for other more common forms of
neurodegeneration.
2. Improving the Central Nervous System (CNS) penetration of
therapeutic substances. In the above-mentioned passive transfer
experiments, anti-prion antibodies had no effect on prion disease in
mice once prion replication had reached the CNS. This was almost
certainly because large bioactive molecules such as antibodies do
not traverse the blood-brain barrier very efficiently. This is a potential
problem for all larger molecules and will limit the impact of many
discoveries in neurobiology. Much work is required to surmount this
additional barrier to effective therapeutics. Very little is known about
the active processes maintaining the integrity of the blood-brain
barrier in health and disease. In order to better understand this,
Professor Hawke has commenced work aimed at identifying the
molecules expressed on brain blood cells (endothelium) in diseases
such as Alzheimer's disease and multiple sclerosis. Work this year
at the University of Sydney has shown that high quality cerebral
endothelium can be purified from sheep and human post-mortem
brain tissue and DNA expression profiling has commenced. Post-
mortem brain tissue samples have been obtained via the Australian
brain donor programs from the University of Melbourne (for Alzheimer
disease brain tissue), the UK Multiple Sclerosis Tissue Bank in
London (for post mortem MS brain tissue), and, for comparison,
brain tissue from subjects without brain disease from the Tissue
Resource Centre at the University of Sydney. Once a profile of the
proteins expressed on cerebral endothelium has been produced,
work will then focus on understanding their contribution to
maintaining the integrity of the blood-brain barrier and if they
can be harnessed for improving the CNS penetration of other
therapeutic substances.
All of the research is conducted by Professor Hawke and his
research team members: Dr Mourad Tayebi, Ms Ariel Arthur
and Ms Rebecca Morton.
