Protein Networks Linked With Neurodevelopmental Disorders

150 proteins affecting cell activity and brain development have been identified by researchers at University of Southern California, which contribute to mental disorders, including schizophrenia, bipolar condition and depression.

It is the first time that these molecules, which are associated with the disrupted-in-schizophrenia 1 (DISC1) protein linked to mental disorders, have been identified. The scientists developed new tools involving stem cells to determine chemical reactions the proteins use to influence cell functions and nerve growth in people.

The findings move science closer to opportunities for treatment for serious mental illness, according to Marcelo P. Coba, the study author and professor of psychiatry at the Zilkha Neurogenetic Institute at the Keck School of Medicine of USC.

Disrupted In Schizophrenia 1

The DISC1 gene was linked to schizophrenia nearly 20 years ago. It controls how neurons develop, as well as how the brain matures.

DISC1 also directs a network of signals across cells that can contribute to the disease. Scientists say errors in these chemical reactions contribute to schizophrenia.

But the identity of proteins that DISC1 can regulate is poorly understood, prompting the USC researchers and colleagues from the State University of New York Downstate Medical Center to undertake the research. The challenge was to simulate conditions inside the human brain, Coba explained.

Using stem cells, they conducted assays resembling habitat where DISC1 does its work. Then, they used CRISPR gene editing to insert a molecular tag on DISC1, allowing them to extract it from brain cells and identify the proteins with which it associates.

Trails To Follow

Identifying the proteins that interact with DISC1 in brain cells could lead to understanding how the risk factors for psychiatric diseases are connected to specific molecular functions, Coba explained. The discovery enables researchers to determine specific processes that differ in patients suffering from specific mental illnesses.

“This gives researchers specific trails to follow within cells from both healthy patients and those diagnosed with disorders,”

Coba said.

Schizophrenia is one of the top 15 leading causes of disability worldwide. People with schizophrenia live an average of nearly 29 years less than those without the disorder, according to the National Institutes of Mental Health (NIMH).

The illness is often accompanied by conditions such as heart disease and diabetes, which contribute to the high premature mortality rate among people with schizophrenia. About 5 percent of people with schizophrenia die by suicide, a rate far greater than the general population, with the highest risk in the early stages of illness, according to the NIMH.

The research was supported by the National Institute of Child Health and Human Development.

Wilkinson B., Evgrafov O., Zheng D., Hartel N., Knowles J.A., Graham N.A., Ichida J. & Coba M.P.
Endogenous Cell Type-Specific DISC1 Interactomes Reveal Protein
Networks Associated to Neurodevelopmental Disorders
Biological Psychiatry (2018), doi: 10.1016/j.biopsych.2018.05.009.