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Researchers discover a way to turn Parkinson protein on itself

Wednesday 30 Oct 19

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Alexander Kai Büll
Professor
DTU Bioengineering

Parkinson's Disease

Parkinson's disease is a long-term degenerative disorder of the central nervous system where brain cells are killed by an abnormal accumulation of a protein in the damaged cells. The cell death disrupts the body’s dopamine signaling system, which causes the Parkinson’s symptoms of e.g. tremors, slow movement, dementia, hallucinations etc.

An estimated seven – 10 million people worldwide have Parkinson’s disease, making it the second most common age-related neurodegenerative disorder after Alzheimer’s disease.  

Researchers have found a way to create a super-inhibitor that effectively stops the development of Parkinsons by using the Parkinson disease itself as an active building block.

Various neurodegenerative diseases such as Parkinson’s are closely linked to the aggregation of individual components called monomers of a specific protein that forms long chainlike fibrils, which kills the brain cells and disrupts the brain’s signaling causing the disease symptoms such as tremors and slow movements and cognitive impairment in the case of Parkinson’s.

Now researchers have found a way to use the building blocks of the chains to create a super inhibitor that stops the aggregation process, thereby stopping the further development of disease symptoms in animal and cell models of Parkinson’s. Professor Alexander Büll says

“I am particularly excited about the fact that we seem to have discovered a new mode of inhibition, where the initial inhibitor forms a complex with the target and the complex itself is an even better inhibitor. In this way, we get an extremely efficient interference with the dangerous fibril formation process.”

The new discovery of the super inhibitor has its roots in a previous study, where Professor Wolfgang Hoyer from Heinrich Heine University Düsseldorf showed that a binding protein called AS69 efficiently prevents fibril formation in the test tube, but the mechanism behind this remained a mystery.

In the current study recently published in the journal eLife, Professor Alexander Büll and his collaborators from Heinrich Heine University Düsseldorf (HHU) and Cambridge University investigated this promising molecule in much more detail.

The researchers found that AS69 captures the monomers and forms complexes with them thereby preventing them from forming the destructive fibrils. Initially they discovered that this inhibition works efficiently, but requires the same number of AS69 molecules, as the number of molecules that are to be inhibited, and it is therefore not very economical.

"I am particularly excited about the fact that we seem to have discovered a new mode of inhibition, where the initial inhibitor forms a complex with the target and that the complex itself is an even better inhibitor. In this way, we get an extremely efficient interference with the dangerous fibril formation process."
Professor Alexander Büll, DTU Bioengineering

When the researchers dived deeper into the mystery of AS69, they found that there is a further property that makes AS69 particularly effective. When AS69 binds to the monomer they transform into a super inhibitor that inhibits the fibril formation much more efficiently than AS69 does on its own.

The researchers have examined the effect of AS69 not only in test tubes but also in cell culture and in animal models. Diseased fruit flies (Drosophila) treated with AS69 displayed notably improved motor skills in a climbing assay. However, Professor Hoyer is still cautious about potential therapeutic use:

“The positive results in living creatures give us hope that we have possibly found a path to an active ingredient through AS69 and other similar molecules. However, it will still be a long time before this could potentially be used for humans.”

Read the publication in eLife An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils


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12 DECEMBER 2019