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Too busy for misfolding Mireille Claessens on causes of Parkinson

Could we keep unstructured proteins in our cells so busy doing their regular job that they cannot fold into the toxic structures leading to diseases like Parkinson and Alzheimer? Simply dissolving the ‘plaques’ that are formed, using medication, doesn’t seem to do the job. Professor Mireille Claessens of the University of Twente therefore wants to know, at what specific locations within the protein structures, an intervention is possible. Her inaugural address, as a Professor of Nanobiophysics, was on 11 April, World Parkinson Day.

It is busy inside our cells, Claessens shows, very busy. With our DNA as a starting point, proteins are formed that fold themselves inside the cell. Shape and function are closely related, as if a designer has been working on it. We know, from diseases like Parkinson and Alzheimer, that proteins can fold in the wrong way as well, leading to cluttered ‘plaques’. This already proves that inside the cell, it is even more complex than following the DNA ‘design rules’ Our cells also have unstructured proteins, that seem a bit messy. One of them is α-synuclein of which we know that it plays a role in neurodegenerative diseases. Which points inside these tangles interact with other proteins, is a question Mireille Claessens would like to have answered. “We’ll search for the most probable locations where it goes wrong, leading to the development of Parkinson. What can we do to recover the balance?” Claessens asks in her inaugural speech.


Transport

The fact that the misfolding of unstructured proteins is playing a major role in developing diseases, is well  known. But why the plaques lead to neurons dying, is still not certain. One theory is that the early aggregated proteins – oligomers – form holes in the cell membrane. Would this be the case, a possible remedy would be medication that dissolves these early tangled structures. This medication could, however, also affect healthy functions of the proteins. Apart from that, it is, again, more complicated than we would expect. So what blocks the brain signals, leading to dying neurons then? There are indications that the transport along the cell membrane, via ‘vesicles’, is affected. Unstructured proteins prove to be able to convert the vesicles into smaller vesicles. What is the consequence of this, is one of the things Claessens would like to clarify.

Better than polymers

Except for the role unstructured proteins play in diseases, they are interesting building blocks if you make them in the lab. When you make a gel out of them, for example, its strength can be varied using temperature. In some ways, they even perform better than polymers. It might be interesting to use a gel like this for cartilage repair and recovery, as cartilage cells are stimulated to form new tissue.

Given the enormous complexity, Mireille Claessens is aware of the fact that there is no single scientist being able to fully grasp all proteins and processes going on, just like no one has a full view on what is happening in a city. Although this work can only be done in a multidisciplinary way, expert knowledge from separate disciplines is required as well: "Knowing just a little bit of everything, will not help solving the big questions."

Mireille Claessens, Professor of Nanobiophysics, held her inaugural address ‘Te druk om te vouwen’ - too busy for folding -', in Dutch, on 11 April at the University of Twente.

ir. W.R. van der Veen (Wiebe)
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