Scientists at the University of Eastern Finland and the Turku Center for Biotechnology say they have found new ways to block a pathway that may be responsible for several brain disorders. They believe their discovery might open the door to developing better treatments.
The NOS-1 protein generates nitric oxide, a chemical signal linked to neurological disorders ranging 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.
The researchers involved in the new work previously found that neurodegeneration caused by NOS-1 requires 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 scientists, who published their study (“Unexpected Heterodivalent Recruitment of NOS1AP to nNOS Reveals Multiple Sites for Pharmacological Intervention in Neuronal Disease Models”) in the Journal of Neuroscience, demonstrated that NOS1AP binds to NOS-1 in a surprisingly complex manner, and they developed two separate ways to prevent it based on their finding 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. The second site was completely unexpected as no similar interaction had been previously described.
“This previously unrecognized heterodivalent interaction of nNOS with NOS1AP may therefore provide distinct opportunities for pharmacological intervention in NOS1AP-dependent signaling and excitotoxicity,” wrote the investigators.
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. The researchers explain that this means that it should now be 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 approaches may be combined. The team reports that it is confident that their work might lead to the development of new drugs for several different neurological diseases and conditions.