Molecular mechanisms of Parkinson’s disease
Ubiquitination is a post-synthesis modification that includes attachment of small regulatory protein ubiquitin to a substrate protein. The addition of ubiquitin can signal to initiate protein degradation or alter their cellular location or affect their activity and promote or prevent protein interactions. Parkin is the enzyme that ubiquitinates mitofusin, a mitochondria and endoplasmic reticulum (ER) resident protein, which bridges mitochondria to the ER. The EU-funded (MITOFUSIN-PD) project focused on the role of parkin in the regulation of the interaction between mitochondria and ER. Balanced ubiquitination and de-ubiquitination of mitofusin might provide a reversible mechanism to control the ER-mitochondria interaction. Consequently, project aimed to identify the protein that opposes parkin in the ubiquitination of mitofusin. Researchers found that the degree of interaction between ER and mitochondria is decreased in parkin deficient cells. The functional counterpart of ER- mitochondria interaction consisting of Ca2+ transfer between the two compartments was decreased in the same cells. This impairment modified Ca2+ signaling and affected processing, folding and proper export of proteins that are synthetized on the ER and are required for cell survival. Researches screened a de-ubiquitination enzyme library to identify enzymes that might oppose parkin in the ubiquitination of mitofusin. They found five potential hits, which expression affected mitofusin steady state and ubiquitinated levels. In particular, downregulation of the de-ubiquitination enzyme Usp8 resulted in decreased mitofusin protein levels and enhanced mitochondria fission. De-ubiquitination enzymes are emerging as very attractive drug therapy candidates. Clinical trials for specific inhibitors of these enzymes have already been approved in cancer therapy. In a similar fashion, de-ubiquitination inhibitors or activators can be beneficial in the treatment of Parkinson’s disease patients
Keywords
Parkinson’s disease, mitochondria, ubiquitination, parkin, mitofusin
