Academic journal

Inactivation of a particular protein complex associated with Parkinson’s disease and anxiety disorders

Inactivation of a particular protein complex that plays a key role in turning off genes leads to nerve cells not producing enough essential neurotransmitters. This could be part of the explanation for diseases such as Parkinson’s disease and anxiety disorders. This is the result of a discovery by researchers from Umeå University, Lund University and Karolinska Institutet.

We have seen that if this protein complex is inactivated, the ability to keep genes that control other functions off is impaired. This, in turn, shuts down genes needed to maintain nerve cell function. In animal studies, we can see a change in animal behavior that is similar to those that occur in Parkinson’s disease.”


Johan Holmberg, Professor in the Department of Molecular Biology, Umeå University, Sweden, one of the lead authors of the study

After neurons form during fetal development, they often retain their identity and function for the rest of life. In addition to the need for genetic programs needed to form and keep the nerve cell active, genes controlling other properties must also be “silent” all the time. The current study shows that this silencing of irrelevant genes depends on a specific protein complex, PRC2.

Without a functioning PRC2 complex, mature neurons that produce the important neurotransmitters dopamine and serotonin gradually lose their identity and function. In Parkinson’s disease, cells that produce dopamine die, while a lack of serotonin is associated with mental health problems. When tested on mice, the researchers observed a gradual change in the mice’s behavior, such as motor symptoms typical of Parkinson’s disease.

“If we can see that the mechanisms controlling gene regulation are part of why diseases that damage the nervous system occur, it could open up exciting new possibilities for diagnosis and treatment, but there’s still a long way to go. way to go,” says Johan Holmberg.

The study was performed by deleting a vital component of the PRC2 protein complex in the nerve cell types of interest in mice. The effects were then investigated using microscopy, behavioral studies, electrophysiology, and a combined analysis of gene expression and changes in histones, the proteins around which long DNA coils chromosomes are coiled.

The researchers now plan to go further and study whether the mechanisms studied in mouse models are indeed involved in neurodegenerative or mental disorders. Furthermore, the researchers want to find out what exactly controls the downregulation of genes when the PRC2 complex is inactivated. An interesting observation made in the study is that the very subtype of dopamine-producing neurons that die in Parkinson’s disease show particular sensitivity to loss of PRC2 activity, and they showed significantly greater changes in the expression of genes than other neurons. One of the things they want to explain is the mechanisms behind this selective sensitivity.

The study is published in the scientific journal Science Advances.

Source:

Journal reference:

Toskas, K. et al. (2022) PRC2-mediated repression is essential for maintaining the identity and function of differentiated dopaminergic and serotonergic neurons. Scientific advances. doi.org/10.1126/sciadv.abo1543.