The Jekyll and Hyde of disease

When we think of illness and its causes, the usual suspects are viruses and bacteria. Causing a range of conditions from food poisoning to hepatitis, we spend a lot of effort trying to eradicate them in the form of better hygiene and vaccinations. Another major disease factor is cancer, having more complex causes and treatments, because it arises from normally functioning cells and their controls going awry.

While it has been known for over a century that bacteria, viruses and parasites cause disease, the newest and smallest infectious agent, the prion, was only identified in the 1980s. Again, a normal part of the body, in this case a protein called a prion in the brain cell membrane, was found to change form and cause a family of fatal neurodegenerative disorders which affect animals and humans, including Bovine Spongiform Encephalopathy (BSE or mad cow disease) and its human form Creutzfeldt-Jakob disease (CJD).

Associate Professor Andrew Hill from the Department of Biochemistry and Molecular Biology and Bio21 Institute, has been working to understand the disease processes of these and other neurodegenerative disorders (such as Alzheimer’s disease) for his whole career. He heads a team investigating how the prion causes the fatal spongy degeneration of the brain, and the devastating dementia associated with these conditions.

Mad cow disease came to prominence in Europe in the late 1980s when around 170,000 cows were affected. During his PhD, Associate Professor Hill revealed that mad cow disease and the human condition variant CJD (vCJD) were linked, caused by exposure to the same strain of prion. Prion diseases are unique in that they can occur sporadically, be inherited through mutations in the prion protein gene or by exposure to infectious prions such as by eating infected meat products and incomplete sterilisation of surgical instruments.

Associate Professor Hill explains that prions are mainly made up of a protein called PrP (prion protein) that has changed its shape. Normally this protein exists in our bodies but when it changes shape, it causes disease – making prion diseases a member of a family of “protein misfolding diseases”.

“The term ‘prion’ was coined by Nobel Prize winner Dr Stanley B. Prusiner in 1982 from the words ‘protein (aceous)’ and ‘infectious’,” says Associate Professor Hill.

Because the prion has no genetic material (DNA or RNA) we believe that the disease is spread by the misfolded prion forcing normal proteins to change into the disease-causing form.

“The problem with such a unique infectious agent for researchers and clinicians is finding new ways to test for, and inactivate them.”

Associate Professor Hill and his team at the Bio21 Institute have been working on new ways to test for prions in infected tissue. A situation recently highlighted by the Government’s plans to free up the import restrictions of beef into Australia, and the fact that there is currently no test that can determine if a sample is 100 per cent prion-free.

Because the mad cow disease prion is extremely difficult to destroy, current testing methods involve digesting all protein-based material in a tissue sample and examining what is “left over”.

“The spongy form of the brain in these conditions is caused by the infectious prions clumping, or aggregating together to produce holes in the brain tissue. What we are working on is a test that labels the aggregated and non-aggregated forms of abnormal and normal proteins respectively. We are using a fluorescent dye for this because the abnormal folding of the prion hides the dye, producing a distinctive pattern.”

The team, working with other Australian and international researchers, have also discovered the key regions involved in the misfolding of the infectious prion. Some species such as rabbits do not contract these neurodegenerative disorders, so by comparing the structure of their normal prions to the infectious ones in species such as cows, cats, gorillas and deer who do contract the conditions, they have been able to identify the sections of the prion responsible for infection and therefore replication.

“We hope that by identifying the regions critical to misfolding, we are closer to a novel, species independent target for prion disease therapeutics,” says Associate Professor Hill.

“The amazing thing is that the more we understand about prions, the more relevant the disease process of mad cow and its related diseases seems to be to many other conditions such as Alzheimer’s and Huntington’s disease.”

Earlier this year, Associate Professor Hill, working with researchers including Dr Danny Hatters, also from the Department of Biochemistry and Molecular Biology/ Bio21 Institute, revealed for the first time a way to visualise disease proteins aggregating in live cells. The team is now able to use fluorescence to visually distinguish the aggregated and non-aggregated forms of the Huntington protein involved in the Huntington’s disease process.

The researchers hope that by literally shedding light on the behaviour of these aggregating proteins that this new method will lead to better ways to study them, as well as earlier diagnostic tools for the range of conditions they cause, including Alzheimer’s, Parkinson’s and Huntington’s diseases, as well as CJD which initially inspired the research.