Promising parkinson drug decoded

The functioning of the brain strongly depends on the performance of our nerve cells. This is why they are regularly verified for their appropriate function – the components of the defective cells are marked, eliminated and recycled. This includes mitochondria, the powers of our cells. Mitochondria’s altered quality control plays a central role in Parkinson’s disease.

The research group led by Malta Gersch at the Max Planck Institute for Molecular Physiology in Dortmund (MPI) has now been able to elucidate the mode of action of a promising inhibitor of the mitochondrial protein associated with Parkinson by designing chimerical proteins.

These results, published in Structural and molecular biology of natureForm an important basis for the development of innovative therapies against Parkinson and others.

“Involuntary trembling movements, combined with reduced muscle force” – this is how British doctor James Parkinson first described the condition known as “trembling paralysis”. Parkinson’s disease, named after him, is the second most common neurodegenerative disease after Alzheimer’s.

To date, there is no causal treatment for Parkinson syndrome – only symptoms can be treated. The disease is caused by a loss of nerve cells in the brainstem and an associated deficiency in dopamine of neurotransmitters. Currently, there is a great hope for the development of new drugs that could regenerate defective nerve cells and thus counter the loss of nerve cells in Parkinson’s disease.

Defective quality control of mitochondria

The exact cause of the death of nerve cells remains clear. However, there are indications that the faults of their mitochondria could be responsible. The nerve cells in particular depend strongly on these organelles, as they require high quantities of energy.

In healthy cells, mitochondria are subject to constant quality control. If they fail, they are marked with protein ubiquitin for cellular degradation by mitophagy. However, it has recently been shown that a defective marking of damaged mitochondria prevents their degradation.

This is caused by certain key enzymes of mitophagy, which are pathologically modified in the hereditary form of Parkinson’s disease.

Protein engineering reveals the action mechanism

An important enzyme of mitophagy is deubiquitinase (DUB) USP30. It removes Ubiquitin marks from defective mitochondria which are intended for degradation.

An inhibitor of this enzyme, which could promote mitophagy and thus improve nervous function, is currently being studied in clinical trials: it is considered a promising candidate for the treatment of Parkinson’s disease and chronic kidney disease. However, the way inhibitors actually operate on the USP30 were not yet known at the molecular level.

“A problem with the USP30 human protein is that it is difficult to” photograph “- its molecular structure is difficult to elucidate. But if you want to see how the inhibitor binds to the protein, you can use X-rays to produce a so-called” diffraction model “of both partners in a crystal.

“However, because the USP30 is very flexible – you could say that it is torillating in front of the camera – it is difficult to crystallize, and its highly mobile structure therefore does not allow a clear image,” explains Gersch, chief of research group at MPI.

Using innovative protein engineering, Gersch and his team have now been able to obtain a detailed image of how an inhibitor binds to the USP30 and specifically deactivates its activity. To do this, Nafizul Kazi, PH.D. The student of the research group and the first author of the study, created a chimerical protein hybrid similar to the legendary minotaur: he incorporated related elements of other proteins of human deubiquitinase in the USP30, thus producing a USP30 “photogenic” variant.

The diffraction images obtained show that the inhibitor interacts with USP30 in two ways: it links to a region previously unknown which opens only with the interaction of the inhibitor with the protein, and at the same time to a hotspot which is also accessible to other inhibitors.

Innovative active substances against neurodegenerative diseases

“The elucidation of the action mechanism of this Parkinson potential drug will not only help to develop it, but also throws the basics of the design of new USP30 drug molecules”, explains Gersch.

Mitichagia and Dub family enzymes also play an important role in other diseases and are associated with a weakened immune system and tumor growth. “Our new chimerical protein strategy could change the situation for the development of new inhibitors against Dubs.

“It will allow us to decipher the structure of other dub proteins relevant to the disease in the context of molecules, opening the possibility of developing new specific liaison inhibitors for a wide range of diseases,” explains Gersch.