Brussels, 09 Mar 2006

New research by an American-Portuguese team has identified a potential new treatment for degenerative neurological disorders, especially Huntingdon's disease (HD) and Parkinson's disease (PD).

The treatment focuses on the abnormal 'protein aggregates' which are believed to be the cause of these diseases. These protein aggregates cause specific brain proteins to fold incorrectly, resulting in degeneration as the cells clump together and die.

There are two standard biological 'cures' for this clumping - proteasomes and molecular chaperones. Proteasomes cut the faulty proteins into small pieces which can then be eliminated; while molecular chaperones shunt the faulty proteins into their correct shape. In cases such as HD and PD, research indicates that the proteasome and molecular chaperon systems may be malfunctioning - HD sufferers are known to have faulty proteasomes.

Inclusion bodies - rather mysterious structures that appear in patients suffering from both HD and PD - contain high quantities of misshapen proteins. Therapies have typically focused on eliminating both the inclusion bodies and misshapen proteins.

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'Our knowledge about the inclusions has grown substantially over the past few years,' said Tiago Outeiro, a Portuguese researcher working will colleagues at MIT and Harvard. 'We no longer look at them as being the ultimate 'bad guys'. Several groups have gathered evidence that inclusions may actually be protective, which in a way is sort of intuitive: the surface area of a large inclusion is a lot smaller that the combined surface area of a large number of smaller inclusions. All this is still speculative, but mounting evidence suggests this may actually be the case.'

The team worked on the basis that the inclusions are part of the solution, rather than the problem, in these neurodegenerative diseases. They located drugs known to increase the number of inclusions and tested them on cells grown in the lab. In results published in the Proceedings of the National Academy of Sciences, they found that while the drugs increased the number of abnormal proteins and inclusions, some of the drugs had the effect of reducing the toxic effects of those proteins.

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This breakthrough in the aetiology of neurodegenerative diseases has initiated several new lines of research. 'Our study opens a lot of doors, and raises important questions in the field. The compounds can also be used as tools to further dissect the mechanisms leading to cell death which underlies the clinical symptoms in Huntington's and Parkinson's disease. It will be important to further understand the exact role of inclusions, how they form, why they form, and how we can prevent or promote their formation. It will be important to investigate the genetics behind inclusion formation, and to model that in animals,' said Dr Outeiro.

'The next steps in our research will be to identify the target/targets, so we can understand the mechanism for cellular toxicity. This, in turn, will enable us to further develop the drugs, for trials in animal models to validate the effectiveness. Eventually, we want to reach a point where we can safely start human trials, but we want to be extremely careful, because when people's lives are involved, that is never too much,' he concluded.

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