Problems in Neuronal Activity Linked to Schizophrenia

Lisa Franchi May 03, 2013

After examining the normal neuronal activity in the brain of healthy individuals, Australian scientists were able to identify a specifically regulated process that when hampered, may lead to schizophrenia.

Published in the international journal Molecular Psychiatry, a study by the University of Queensland found that such neuronal process involves a specific class of genes called ’long non-coding RNAs’. For DNA to act, it must first be transcribed into RNA – nucleic acids that form a variety of long and short molecules. Some of these molecules are literally ’translated’ or encoded into chains of amino acids to perform specific functions in the cells. However, others do not get translated. This is the first time that the process of transcribing DNAs to RNAs has been found to be regulated by a basic neuronal activity. According to the researchers, levels of the long non-coding RNA called ’Gomafu’ are dramatically reduced when a neuron is activated in the normal brain.

For decades, scientists have considered this long non-coding RNA as junk. But in the current study, it was found that the Gomafu is essential in regulating RNAs. The team, headed by Dr Guy Barry from the Institute for Molecular Bioscience at the University of Queensland and Professor John Mattick from Sydney’s Garvan Institute of Medical Research, found that certain proteins linked with schizophrenia tend to bind strongly with Gomafu. Low levels of Gomafu were observed in the post-mortem examination in the brains of people with schizophrenia.

For the study, the researchers extracted pluripotent human stem cells (IPS cells) which differentiate into cortical-type neurons. These neurons were stimulated using potassium chloride to mimic normal neuronal activity. It was initiated to significantly reduce Gomafu levels. Through a protein microarray approach, the researchers were able to scan all known proteins against Gomafu to see which bound and which did not. They were able to confirm one binding partner that was previously associated with schizophrenia.

Normal Brain vs. Schizophrenic Brain

Dr Barry argued that in the healthy brain, the long non-coding RNAs help bring together the various components in the cell, such as the RNA, DNA or protein by creating a kind of molecular functional scaffold. When Gomafu gets degraded by a signal, it releases all kinds of components into the cell to perform a particular function. But when Gomafu levels are restored, it binds the components once more and then waits for another activation signal.

But in the schizophrenic brain, Gomafu levels are consistently low which causes havoc within the cell. This leads to the splicing and breaking free of proteins, which in normal circumstances, should have been bound to Gomafu.

Schizophrenia is a serious mental illness characterised by the breakdown of thought processes, resulting to varying symptoms, including paranoia, delusion, and hallucinations. "It’s impossible to treat a disease when you don’t fully understand the mechanisms that underpin it.” says Dr Barry. The understanding that long non-coding RNAs are regulated by neuronal activity and is associated with schizophrenia provides opportunities to tackle better treatment options in the future, he added.

Source of this article:

The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing