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Elucidation of the mode of action of a promising drug candidate lays the foundation for the development of targeted therapies for Parkinson's disease and chronic kidney disease
How well our brain functions depends heavily on the performance of our nerve cells. That is why they are regularly checked for their proper function – defective cell components are marked, disposed of and recycled. This includes the mitochondria, the powerhouses of our cells. Impaired quality control of mitochondria plays a central role in Parkinson's disease. The research group led by Malte 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 Parkinson's-associated mitochondrial protein USP30 by designing chimeric proteins. These findings form an important basis for the development of innovative therapeutics against Parkinson's and other diseases.
“Involuntary tremulous movements, combined with reduced muscle strength.” This is how the British physician James Parkinson first described the condition known as “shaking palsy.” 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's syndrome – only symptoms can be treated. The disease is caused by a loss of nerve cells in the brain stem and an associated deficiency of the neurotransmitter dopamine. Currently, there is great hope for the development of novel drugs that could regenerate defective nerve cells and thus counteract the loss of nerve cells in Parkinson's disease.
Faulty quality control of the cellular powerhouses
The exact cause of nerve cell death remains unclear. However, there are indications that defects in their mitochondria could be responsible. Nerve cells in particular are highly dependent on these organelles, as they require high amounts of energy. In healthy cells, the mitochondria are subject to constant quality control. If they fail, they are marked with the protein ubiquitin for cellular degradation by mitophagy. However, it has recently been shown that faulty marking of damaged mitochondria prevents their degradation. This is caused by certain key enzymes of mitophagy, which are pathologically altered in the hereditary form of Parkinson's disease.
Protein engineering reveals the mechanism of action
An important enzyme in mitophagy is the deubiquitinase (DUB) USP30. It removes ubiquitin marks from defective mitochondria that are destined for degradation. An inhibitor of this enzyme, which could promote mitophagy and thus improve nerve function, is currently being investigated in clinical trials: it is considered a promising candidate drug for the treatment of Parkinson's disease and chronic kidney disease. However, inhibitors actually work on USP30 was not yet known on the molecular level. “One problem with the human protein USP30 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 pattern” of the two partners in a crystal. However, because USP30 is very flexible – you could say it wriggles around in front of the camera – it is difficult to crystallise, and its highly mobile structure thereby does not allow for a sharp image,” explains Malte Gersch, research group leader at the MPI. Using innovative protein engineering, Gersch and his team have now been able to obtain a detailed picture of how an inhibitor binds to USP30 and specifically switches off its activity. To do this, Nafizul Kazi, PhD student in the research group and first author of the study, created a chimeric protein hybrid similar to the legendary Minotaur: he incorporated related elements from other human deubiquitinase proteins into USP30, thus producing a ‘photogenic’ USP30 variant. The diffraction images obtained show that the inhibitor interacts with USP30 in two ways: it binds to a previously unknown region that only opens up through the interaction of the inhibitor with the protein, and at the same time to a hotspot that is also accessible to other inhibitors.
Innovative active substances against neurodegenerative diseases
“Elucidating the mechanism of action of this potential Parkinson's drug will not only help to further develop it, but also lay the foundation for designing new drug molecules against USP30,’ says Gersch. Mitophagy and enzymes from the DUB family also play an important role in other diseases and are associated with a weakened immune system and tumour growth. “Our new strategy of chimeric proteins could be a real game changer for the development of new inhibitors against DUBs. It will enable us to decipher the structure of other disease-relevant DUB proteins in complex with molecules, opening up the possibility of developing new specific binding inhibitors for a wide range of diseases,’ says Malte Gersch, looking to the future.
Dr. Malte Gersch
Group Leader, Max Planck Institute of Molecular Physiology
Tel.: +49 231 133 2943
email: Malte.Gersch@mpi-dortmund.mpg.de
Kazi NH, Klink N, Gallant K, Kipka GM, Gersch M (2025). Chimeric deubiquitinase engineering reveals structural basis for specific inhibition of USP30 and a framework for DUB ligandability. Nat. Struct. Mol. Biol. doi: 10.1038/s41594-025-01534-4
https://www.mpi-dortmund.mpg.de/news/promising-parkinson-s-drug-decoded
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