Study associates schizophrenia with defective processing of messenger RNA in cells

September 6, 2017 by Karina Toledo
Confocal microscope image of cultured human oligodendrocytes. The differential expression of hnRNPs may lead to dysfunction of oligodendrocytes, glial cells that produce myelin and are important for neuronal activity. Credit: Daniel Martins-de-Souza, University of Campinas

Schizophrenia affects approximately 1 percent of the world's population and is the main cause of psychiatric incapacitation. Despite its high prevalence and the severity of its symptoms, little is known about the biochemical mechanisms involved in its development or progression.

A study published in Molecular Neuropsychiatry suggests that many of the brain alterations found in patients with schizophrenia may be rooted in the dysfunctional participation of the so-called spliceosome, a complex directly involved in the process of protein synthesis.

"Our study is the first to link the spliceosome with the disease," says Daniel Martins-de-Souza, a professor in the Biology Institute of the University of Campinas (IB-UNICAMP), São Paulo State, and principal investigator for the project, which receive support from the São Paulo Research Foundation (FAPESP)

At the cell level, proteins are synthesized through a process in which DNA information is transcripted by messenger RNA and then spliced by the spliceosome, whose role is to unite the codifying parts of the genetic code to the precursor molecule, therefore shaping the protein to its functional form.

According to Verônica Saia-Cereda, Unicamp doctoral student and first author of the article, malfunctioning of the messenger RNA processing machinery could mean that certain proteins are not translated correctly and that their expression is altered throughout the organism with unknown consequences.

On a post-mortem brain tissue comparative analysis between 12 and 8 healthy individuals, Martins-de-Souza group detected a high amount of proteins with modified expression at two brain regions that previous research has shown to be morphologically and functionally altered in patients with schizophrenia, the anterior temporal lobe and the .

"The anterior temporal lobe is involved in auditory and visual processing, so it's closely linked to symptoms such as psychosis and hallucinations. The corpus callosum is the brain region that contains the most glial cells [such as astrocytes, microglia, and oligodendrocytes]," Martins-de-Souza said.

Oligodendrocytes are crucial for synapses, as they produce a fatty substance called myelin. Propagation of electric impulses among neurons is impaired in the absence of an insulating myelin sheath.

With the aid of a mass spectrometer, the scientists could map all the proteins found in the nuclei of the cells in these two and isolating them for analysis, excluding proteins found in other organelles and in the cytoplasm. In the corpus callosum, they found 119 differentially expressed proteins, 24 of which were nuclear proteins. According to Saia-Cereda, most are involved in calcium-mediated cellular signaling, which is important both to the metabolism of mitochondria (organelles that produce energy for the cell) and to the removal of surplus amounts of the neurotransmitter dopamine from the synaptic vesicle (where information exchange between neurons occurs).

"Alterations in dopamine levels in the brain are associated with the most characteristic symptoms of schizophrenia, such as delirium and hallucinations," Saia-Cereda said.

In the anterior temporal lobe, they found 224 differentially expressed proteins; 76 were nuclear proteins. Eight of these nuclear proteins are involved in the functioning of the spliceosome—including those that are part of the heterogeneous nuclear ribonucleoprotein (hnRNP) family, produced by oligodendrocytes. In 2005, Martins-de-Souza's group found that the expression of hnRNP proteins was also altered in schizophrenia patients.

"Subsequent studies performed by other groups on the basis of our findings showed in animal and cellular models that alterations in hnRNPs do indeed interfere in the neuron myelination process and may impair cerebral connectivity," said Martins-de-Souza. "Therefore, this may be the genesis of the myelination dysfunctions associated with schizophrenia."

In another study, postdoctoral student Mariana Fioramonte is working to identify the proteins that partner with hnRNPs to process messenger RNA. Martins-de-Souza, her supervisor for the project, explained that the aim is to determine whether the proteins that associate with hnRNPs for this function are different in patients with and people without mental disorders. "The next step will be to try to modulate the expression of these molecules in the laboratory and observe how the spliceosome functions when some of them are inhibited," he said. "The idea is to try to find the cause of this dysregulation of the spliceosome. Depending on the results, it's possible that some of these proteins can be tested as therapeutic targets."

Explore further: Prenatal lack of omega-3 and omega-6 fatty acids linked to schizophrenic symptoms in mice

More information: Verônica M. Saia-Cereda et al. The Nuclear Proteome of White and Gray Matter from Schizophrenia Postmortem Brains, Molecular Neuropsychiatry (2017). DOI: 10.1159/000477299

Related Stories

Prenatal lack of omega-3 and omega-6 fatty acids linked to schizophrenic symptoms in mice

September 5, 2017
Researchers at the RIKEN Brain Science Institute in Japan have discovered a process through which changes in nutrition during early mouse pregnancy lead to offspring that develop schizophrenic-like symptoms as adults. Published ...

Structure that edits messenger RNA transcripts defective in two different forms of motor neuron diseases

April 26, 2013
Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are degenerative motor neuron diseases in which the key mutated genes are involved in RNA metabolism. This similarity suggests that a common dysregulation ...

New study reveals how RNA splicing errors may spark the development of both ALS and a form of dementia

June 13, 2017
The most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)—rare and related neurological disorders marked by progressive deterioration of motor or cognitive abilities—may ...

Nerve-signaling protein regulates gene associated with schizophrenia

January 6, 2017
Researchers from the University of California, San Diego, have identified a protein that regulates a gene associated with schizophrenia. The study, published in the Journal of Neurophysiology, was chosen as an APS select ...

Protein findings open new avenues to understanding and treatment of schizophrenia

November 9, 2015
Stem cells from adult schizophrenia patients form new proteins more slowly than those from healthy people, according to new research.

Highly organised protein structure implicated in schizophrenia

November 10, 2014
Schizophrenia is associated with enormous personal, familial and societal cost. Exactly how genetic and environmental risk factors act together to lead to the development of schizophrenia is as yet unknown. As a result, current ...

Recommended for you

Research redefines proteins' role in the development of spinal sensory cells

September 19, 2017
A recent study led by Samantha Butler at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA has overturned a common belief about how a certain class of proteins in the spinal cord regulate ...

The brain at work: Spotting half-hidden objects

September 19, 2017
How does a driver's brain realize that a stop sign is behind a bush when only a red edge is showing? Or how can a monkey suspect that the yellow sliver in the leaves is a round piece of fruit?

Team discovers how to train damaging inflammatory cells to promote repair after stroke

September 19, 2017
White blood cells called neutrophils are like soldiers in your body that form in the bone marrow and at the first sign of microbial attack, head for the site of injury just as fast as they can to neutralize invading bacteria ...

Epileptic seizures show long-distance effects

September 19, 2017
The area in which an epileptic seizure starts in the brain, may be small but it reaches other parts of the brain at distances of over ten centimeters. That distant activity, in turn, influences the epileptic core, according ...

Study uncovers markers for severe form of multiple sclerosis

September 18, 2017
Scientists have uncovered two closely related cytokines—molecules involved in cell communication and movement—that may explain why some people develop progressive multiple sclerosis (MS), the most severe form of the disease. ...

Genetically altered mice bear some hallmarks of human bipolar behavior

September 18, 2017
Johns Hopkins researchers report they have genetically engineered mice that display many of the behavioral hallmarks of human bipolar disorder, and that the abnormal behaviors the rodents show can be reversed using well-established ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.