Parkinson's disease is a neurodegenerative disease for which there is still no cure. The disease is caused by a loss of nerve cells in the brain stem and an associated deficiency of the neurotransmitter dopamine. The exact cause of the nerve cell death is still unknown. However, there are indications that defects in their mitochondria could be responsible.

Quality control is of central importance for maintaining a healthy mitochondrial population - which are the power plants of the cells. Two genes that code for the enzymes mitochondrial PINK1 and the ubiquitin ligase Parkin are responsible for the degradation of damaged mitochondria. In this pathway, PINK1 recognizes the damage to the mitochondria and activates Parkin by phosphorylating Parkin and ubiquitin. Activated Parkin then builds ubiquitin chains on damaged mitochondria to mark them for degradation in lysosomes.⁽¹⁾ This recycling mechanism is disrupted in Parkinson's disease.⁽²⁾

The enzyme USP30 deubiquitinase acts as a brake on mitophagy by counteracting Parkin-mediated ubiquitination and thus the selective autophagy of damaged mitochondria. For therapeutic treatment, an investigation into the possibilities of inhibiting USP30 appears to make sense. An inhibitor of the enzyme, which could promote mitophagy and thus improve nerve function, is currently being investigated in clinical trials. However, the molecular basis for the specific inhibition of USP30 by small molecules has not yet been clarified because the mode of action could not be visualized.

In the presented work, the research team from Dortmund succeeded in making this groundbreaking progress. The team incorporated related elements from other human deubiquitinase proteins into USP30, thus creating a “photogenic” USP30 variant. They used HEK293 and HeLa cells for their studies. The images obtained show that the inhibitor interacts with USP30 in two ways, by binding to a previously unknown area and at a site that is also accessible to other inhibitors.

Original publication:
Kazi NH, Klink N, Gallant K, Kipka GM, Gersch M. Chimeric deubiquitinase engineering reveals structural basis for specific inhibition of the mitophagy regulator USP30. Nat Struct Mol Biol. 2025 May 5. doi: 10.1038/s41594-025-01534-4. Epub ahead of print. PMID: 40325251.

Source:
https://www.mpi-dortmund.mpg.de/aktuelles/vielversprechender-parkinson-wirkstoff-entschluesselt

Further information:
⁽¹⁾ Bingol B, Sheng M. Mechanisms of mitophagy: PINK1, Parkin, USP30 and beyond. Free Radic Biol Med. 2016 Nov;100:210-222. doi: 10.1016/j.freeradbiomed.2016.04.015. Epub 2016 Apr 16. PMID: 27094585.
⁽²⁾ Sven Geisler, Kira M. Holmström, Diana Skujat, Fabienne C. Fiesel, Oliver C. Rothfuss, Philipp J. Kahle and Wolfdieter Springer (2010). PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nature Cell Biology advance online publication 24.01.2010: dx.doi.org/10.1038/ncb2012.
https://healthcare-in-europe.com/de/news/neue-erkenntnisse-zur-entstehung-der-parkinson-erkrankung.html