Researchers Discover New Ways to Shut Down Signals Involved in Brain Diseases

18.05.2015

A research team based at the University of Eastern Finland and the Turku Centre for Biotechnology have found new ways to block a pathway that may be responsible for several brain disorders, which could open the door to developing better treatments.

The protein NOS-1 generates nitric oxide, a chemical signal that is linked to neurological disorders from neurodegeneration, stroke and chronic pain sensitivity to anxiety and depressive disorders.

– These are now among the most common causes of disability and mortality, but decades of efforts have not led to a safe drug that controls NOS-1, says senior researcher Michael Courtney from the Centre for Biotechnology at the University of Turku and Åbo Akademi.

The researchers hope that continuation of their work could lead to improved treatments for neurological conditions such as stroke and chronic pain as well as depressive and anxiety disorders. As the proteins targeted are associated with schizophrenia and sudden cardiac death, future research in this area may even assist the treatment of a wider range of diseases.

Researchers were surprised to find two separate sites of interaction

The researchers involved in the new work previously found that neurodegeneration or brain lesions caused by NOS-1 requires the binding of NOS-1 to it to bind another protein called NOS1AP (or CAPON). They asked if damage can be reduced by preventing binding of NOS1AP to NOS-1, as NOS-1 cannot directly be controlled by drugs.

The researchers now reveal NOS1AP binds to NOS-1 in a surprisingly complex manner, and developed two separate ways to prevent it.

– By studying precisely how NOS1AP binds to NOS-1 they found two separate sites of interaction, by demonstrating that two different parts of NOS1AP are required for binding to NOS-1 on separate sites. Each site could be blocked, one by a peptide previously developed by the team and the other by a new synthetic protein generated for this study, Courtney says.

The second site was completely unexpected as no similar interaction had been previously described and so nobody had known to look for it before. Blocking either site by itself reduced the damaging signals caused by NOS1 in brain cells. The results were replicated in several regions of brain tissue that are sensitive to degeneration caused by NOS-1.

– This means that it is now easier to design drugs that control damaging signals from NOS-1 in the brain because it can be done in two different ways or both ways may be combined. This might lead to development of new drugs for several different neurological diseases and conditions, Courtney says.

This research, published in the 13th May issue of the Journal of Neuroscience, was funded by the Academy of Finland, the European Union, the University of Eastern Finland, The Finnish Cultural Foundation North Savo Regional Fund, The Magnus Ehrnrooth Foundation and the University of Turku.

>> Link to the article: http://www.jneurosci.org/content/35/19/

Created 18.05.2015 | Updated 20.05.2015

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