Schizophrenia May Be Caused by Damage To The “Protective Coat” of Neurons

The study investigated how a protein called hnRNP A1, which helps control the production of other proteins in the brain, influences the recovery of myelin, a substance that protects neurons. Using mice, scientists blocked this protein and saw that this affected several important brain functions, such as communication between neurons and processes linked to memory. Despite this, the mice showed no changes in behavior. The research helps to better understand how certain problems in brain cells can be linked to diseases such as multiple sclerosis and Alzheimer's.

Oligodendrocytes are cells in the brain and spinal cord that have a very important function: they produce myelin, a substance that forms a kind of “protective cover” around neurons. This cover helps electrical impulses travel quickly and efficiently through the nervous system.

During brain development, oligodendrocytes are essential for forming this protection. And, if any damage occurs, as in certain diseases, they also try to repair this myelin.

However, when these cells are damaged or die, it can cause or worsen diseases such as multiple sclerosis, Alzheimer’s disease, and even disorders such as schizophrenia.

One of the things that can disrupt the functioning of oligodendrocytes is a special group of proteins called RBPs, or RNA-binding proteins. These proteins act as “translators” of genetic information, helping cells understand and correctly use what is written in DNA to produce other important proteins.

Oligodendrocyte in white

In some neurological diseases, these RBP proteins do not function as they should. Sometimes they are in the wrong places within the cell, or are produced in quantities different from normal, either too much or too little. When this happens, the cell's balance is broken, which can disrupt its function and even contribute to the development of brain diseases.

Among the RBPs, there is a group called hnRNPs. These proteins work within the oligodendrocytes themselves and help with several important tasks.

They influence the growth and multiplication of these cells, and also participate directly in the production of substances essential for the formation of myelin, such as the proteins MBP and PLP, which are fundamental components of this “protective cover” of neurons.

Some hnRNPs, for example, are responsible for taking the genetic material to the right place within the cell, where myelin will be produced. Others control the timing and quantity of this production.

Recent research has discovered that one of these proteins, called hnRNP A1, may be altered in diseases such as multiple sclerosis. When this happens, it may be related to the loss of myelin and even the death of these cells.

Another very important function of these proteins is "splicing", a process that works like editing RNA (which is like a copy of DNA instructions). This editing allows the cell to produce different versions of the same protein from a single gene.

hnRNP A1 plays a fundamental role in this editing process, and interacts with other proteins to ensure that the right versions are made at the right time. This is essential for the proper functioning of cells and can influence the onset or worsening of neurological diseases when something goes wrong.

In this specific study, researchers wanted to understand what happens when hnRNP A1 activity is inhibited in the brains of mice. To do this, they used a substance called cuprizone, which causes the loss of myelin in specific regions of the brain, simulating what happens in diseases such as multiple sclerosis.

They then administered an experimental drug called VPC-80051, which blocks the splicing action of hnRNP A1, to analyze how this affects myelin recovery in the following weeks.

Scientists from the University of Campinas, Brazil, studied three important areas of the brain: the corpus callosum (which connects the two sides of the brain), the prefrontal cortex (linked to functions such as thinking, emotions and behavior) and the hippocampus (fundamental for memory).

They analyzed the proteins present in these regions after treatment, to understand how hnRNP A1 activity impacts the myelin recovery process and the overall functioning of the brain.

(A) Schematic drawing showing how the experiment was conducted to study the effects of cuprizone, a substance used to cause myelin loss in the brain.

(B) Images of the brain, specifically of a region called the corpus callosum, stained with a special dye that highlights myelin. Comparing the groups: the mice that received cuprizone showed a clear reduction in myelin after five weeks. However, after the recovery phase, it was possible to see an improvement in the amount of myelin.

(C) Images with fluorescence staining (a type of marking that glows under special light), also of the corpus callosum. They show the difference between the brains of the animals that did not receive the substance and those that were treated with cuprizone, both at the time of greatest myelin loss (week 5) and in the recovery phase (week 10).

The results showed that, by blocking this protein, several other proteins involved in the formation of myelin were affected. Furthermore, biological pathways related to the functioning of synapses (places where neurons communicate), memory and the chemical balance of the brain were also altered.

This indicates that hnRNP A1 has a broader role than previously thought, influencing not only the production of myelin, but also communication between neurons.

Even with these changes at the molecular level, the mice did not show any changes in behavior during the tests, which suggests that the observed effects may be occurring in a subtle way, or not yet intense enough to generate visible symptoms.

In any case, the study provided important new clues about how certain proteins control brain function, and how they may be involved in neurodegenerative diseases. This data may help develop new treatments in the future.

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Impacts of hnRNP A1 Splicing Inhibition on the Brain Remyelination Proteome

Caroline Brandão-Teles, Victor Corasolla Carregari, Guilherme Reis-de-Oliveira, Bradley J. Smith, Yane Chaves, Aline Valéria Sousa Santos, Erick Martins de Carvalho Pinheiro, Caio C. Oliveira, Andre Schwambach Vieira, Fernanda Crunfli, Daniel Martins-de-Souza

Journal of Neurochemistry. Volume169, Issue1 January 2025 e16304

https://doi.org/10.1111/jnc.16304

Abstract

Oligodendrocytes, the myelinating cells in the central nervous system, are implicated in several neurological disorders marked by dysfunctional RNA–binding proteins (RBPs). The present study aimed at investigating the role of hnRNP A1 in the proteome of the corpus callosum, prefrontal cortex, and hippocampus of a murine cuprizone–induced demyelination model. Right after the cuprizone insult, we administered an hnRNP A1 splicing activity inhibitor and analyzed its impact on brain remyelination by nanoESI-LC-MS/MS label-free proteomic analysis to assess the biological processes affected in these brain regions. Significant alterations in essential myelination proteins highlighted the involvement of hnRNP A1 in maintaining myelin integrity. Pathways related to sphingolipid and endocannabinoid signaling were affected, as well as the synaptic vesicle cycle and GABAergic synapses. Although behavioral impairments were not observed, molecular changes suggest potential links to memory, synaptic function, and neurotransmission processes. These findings enhance our understanding of the multifaceted roles of hnRNP A1 in the central nervous system, providing valuable insights for future investigations and therapeutic interventions in neurodegenerative and demyelinating diseases.