A molecular switch that controls the behavior of a protein that, when altered, increases vulnerability to schizophrenia and mood disorders has been identified in new research. The findings make possible the creation of biomarkers that can help diagnose mental illness and track treatment.
The new research, led by Akira Sawa, M.D., Ph.D., professor of psychiatry and behavioral sciences at Johns Hopkins, appears to answer why the Disrupted In Schizophrenia gene (DISC1) and its protein product have so many distinct roles in the development and functioning of the brain.
The research team discovered one specific protein variation that governs DISC1’s two most important functions: regulation of new neuron development in the cerebral cortex (thinking part of the brain), and the programmed migration of these neurons, vital for the formation of the brain’s architecture.
If the switch has problems — if it lets in too many new neurons or there’s not enough migration, for example — the brain may not develop properly, leaving it primed for the development of mental illness.
According to Sawa, the switch seems to alter the function of DISC1 from its role in building new neurons to its role in neuron migration. This happens when the protein is changed through a biochemical process called phosphorylation, or attachment of a phosphate to the protein, he says.
“It seems that just one specific protein modification is a key determinant that accounts for the two most important functions of this molecule,” Sawa said.
The research is significant because, Sawa said, finding a way to spot and track this molecular switch may help with diagnosis, which currently relies on patient behavior.
To find the switch, researchers looked at tissue samples using mass spectrometry. Using a generated antibody, they discovered that some of the protein had been changed and some had not.
It was discovered that the unmodified DISC1, and not the modified form, was required to regulate new neurons. The opposite was true for neural cell migration: the modified version of DISC1 bound to other proteins was involved in cell movement, but not the unmodified version.
The team confirmed their findings by using an antibody capable of finding this protein modification in mice. The antibody was used on the brains of fetal mice at embryonic day 14, when neurons are being generated. Researchers then found that unmodified DISC1 was the predominant form of the protein. On day 18, when the mouse brain neurons typically are migrating, the team found mostly modified DISC1. Therefore, researchers conclude that the modification acts a switch to determine whether DISC1 is involved in neurogenesis or cell migration.
Mouse models of schizophrenia closely mimic certain key biological processes of human schizophrenia, said Sawa. His team has already developed a version of the antibody that can be used to test for the presence of the protein in human brain tissue.
The findings are published online in the journal Nature.
Source: Johns Hopkins Medicine