Horseshoe-shaped 'Parkinson's' proteins form clumps

More news has come to light about the alpha-Synuclein protein that plays an important role in Parkinson's disease. Biophysicist Martina Huber and colleagues show how these proteins clump together when they come into contact with a membrane. Their article in the Journal of the American Chemical Society (JACS) is now online.

Plaques

Parkinson's disease is characterised by an accumulation of proteins, known as plaques, in the brain. The main constituent of these plaques is the protein alpha-Synucleine, known in short as αS. ‘But exactly what role the protein plays in the brain is not yet clear,' says Huber. Researchers also differ in their opinion of the purpose of these plaques.

The raised edge of the horseshoe can easily fill the space between two raised edges of another horseshoe. This creates a stable aggregate of aS molecules.

Binding to a membrane

What they do agree is that interaction with nerve membranes is important for the biological functioning of aS, and therefore also for the development of Parkinson's. Huber and her colleagues have demonstrated previously that the normally unstructured protein, with its 140 amino acids relatively small, suddenly takes on a clear shape when it binds to a membrane. Two pieces of it twist into a corkscrew shape, the so-called a-helix, and an intermediate section remains the same as it was. It binds to the membrane in a horseshoe shape.

Clumping

Now the researchers demonstrate in their article in the Journal of the American Chemical Society (JACS) that the αS not only changes structure, but also that several of the proteins clump together on interaction with a membrane. A detailed model shows the exchange between the proteins. 'This may also be one of the reasons why aS adopts this horseshoe shape,' explains the Leiden biophysicist. 'A raised edge of the horseshoe can easily fill the space between two raised edges of another horseshoe. This creates a stable aggregate of aS moledules.'

Unique technique

The existence of protein aggregates is nothing new. But to date there has been no way of determining precisely how this process works. The method used by the Leiden biophysicists, pulsed electron spin resonance (ESR), is unique in the Netherlands and has been developed further over a number of years. 'It allows us to observe interactions between proteins on a very small scale and also very specifically. Without this technique it would never have been possible to develop the model.'

Patients

The important question is when this research will start to benefit Parkinson's patients? 'That's something I daren't comment on,' says Huber. 'Let's first see under what specific conditions the interactions we have shown take place. That will occupy us for some time to come.'

Collaboration and financing

The research is a collaboration between the ESR group in Leiden and Vinod Subramaniam's research group at the University of Twente, and is financed by the Foundation for Fundamental Research of Materials (FOM) and the Netherlands Organisation for Scientic Research (NWO).

"A stable lipid-induced aggregate of alpha-Synuclein"

Author(s): Drescher, Malte; van Rooijen, Bart; Veldhuis, Gertjan; Subramaniam, Vinod; Huber, Martina, Journal of the American Chemical Society (JACS) 3 March 2010.