Two blood markers for schizophrenia!

Schizophrenia is a psychiatric disorder whose clinical manifestations are extremely heterogeneous, which makes diagnosis difficult, and suggests that several neurobiological mechanisms are involved. Patient stratification, based on reliable biomarkers, would allow to better target available treatment options. To this end, the group, carried out a translational study in patients and experimental model, focusing on the mitochondria of the parvalbumin neurons.

Mitochondria are organelles responsible for producing the energy cells need to function normally. They use oxygen to do this, releasing highly toxic molecules called "free radicals. These have to be eliminated to avoid irremediable damage by oxidation, i.e. oxidative stress. The antioxidant system takes on this task. The brain, an important producer of free radicals, is very sensitive to deregulations of the antioxidant system. "We know that an essential antioxidant produced by the human body, called glutathione, is deficient in schizophrenic patients", explains the senior author. "This deficiency and the resulting imbalance between free radicals and antioxidants (called redox dysregulation) lead, among other consequences, to an alteration of parvalbumin neurons, a type of neurons that is directly involved in all cognitive functions".

To conduct its studies, the group works with an animal model of schizophrenia, in which the level of cerebral glutathione is lowered. "This animal model is not designed to mimic a human disease in all its complexity, but to reproduce a typical abnormality and investigate its consequences."

 Thanks to this animal model, it has been possible to observe that impaired mitochondria accumulate in parvalbumin neurons in the prefrontal cortex. "Normally, they’re eliminated or recycled, so that the "cleaning system" is no longer functional" adds the first author of the article published in Molecular Psychiatry.

Mitochondria are generally able to eliminate their damaged parts by splitting, using a mechanism called mitophagy. This process involves a series of molecules whose production is controlled by miR137, a microRNA that plays a key role in their regulation. The authors succeeded in demonstrating that the level of miR-137 was very high in the model, as was oxidative stress. In parallel, an element of cellular respiration expressed specifically by parvalbumin neurons, the COX6A2 molecule is decreased. "In other words, the mitochondria of parvalbumin neurons are dysfunctional following the increase in oxidative stress, and it can be shown through analyzing the levels of miR-137 and COX6A2 in the blood".

In their attempts to intervene directly on the free radicals produced by mitochondria, the neuroscientists showed, in the animal model, that the alterations of these two molecules, miR137 and COX6A2, can be completely corrected by an antioxidant compound that specifically targets mitochondria, called MitoQ. The research team was able to demonstrate that treatment with MitoQ also increases the survival and functionality of parvalbumin neurons in the prefrontal cortex.

"Given these promising results, the same compound will be tested in humans as an additional treatment in the early phase of the disease. It’s an important step forward!" says the lead author.

By analysing the blood of patients diagnosed with psychosis, the group was able to determine the levels of miR137 and COX6A2 in the brain. Using these two molecules as biomarkers, they succeeded in demonstrating that among the great heterogeneity of schizophrenia patients there are two major and distinct groups, those with and those without mitochondrial impairments. In addition, the mitochondrial abnormalities are associated with cognitive impairments and the corresponding clinical symptoms: loss of autonomy and reduced social skills. "Patients suffering from a mitochondrial deficiency have more severe clinical symptoms than others", explains the lead. 

The study thus revealed two biomarkers that would make it possible to accurately select patients who are likely to benefit from a treatment targeting the deregulation of cerebral mitochondria. "Our work paves the way for a precise diagnosis and an early, individualised treatment for people with a high clinical risk", concludes the senior author.