The study supports the hypothesis that mitochondrial dysregulation contributes to the development of schizophrenia

Researchers at Rutgers University and Emory University are gaining insights into how schizophrenia develops by examining the strongest known genetic risk factor.

When a small portion of chromosome 3 is missing – known as 3q29 deletion syndrome – it increases the risk of developing schizophrenia about 40-fold.

The researchers have now analyzed the overlapping patterns of altered gene activity in two models of 3q29 deletion syndrome, including mice where the deletion was engineered with CRIPSR, and human brain organoids, or 3D tissue cultures used to study the disease. Both systems display impaired mitochondrial function. This dysfunction can cause a lack of energy in the brain and lead to psychological symptoms and disorders.

said Jennifer Mull, assistant professor of psychiatry, neuroscience, and cell biology at Rutgers Robert Wood Johnson School of Medicine and co-lead author of a study published in the journal Science advances. “The interaction between mitochondrial dynamics and neuronal maturation is an important area for further detailed and rigorous study.”

Mulle, a member of the Center for Advanced Biotechnology and Medicine at Rutgers, and colleagues first showed that a 3q29 deletion was a risk factor for schizophrenia in 2010. The findings converge with work on another genetic risk factor for schizophrenia, 22q11 deletion syndrome (or DiGeorge syndrome). ), which was also found to involve impaired mitochondrial function.

“For genetic variants associated with schizophrenia, we want to understand the underlying pathology at the cellular level,” said Ryan Purcell, assistant professor of cell biology at Emory University School of Medicine and co-lead author of the study. “This gives us a foothold, which may help cut through the polygenic complexity of schizophrenia and better understand its neurobiology.”

About 1 in 30,000 people are born with 3q29 deletion syndrome. In addition to an increased risk of schizophrenia, 3q29 deletion can include intellectual disability, autism spectrum disorder, and congenital heart defects. The effect of the 3q29 deletion on schizophrenia risk is considered to be greater than that of any known single gene variant, but the contributions of individual genes to the deletion are still being analyzed.

The finding that various chromosomal deletions associated with schizophrenia impair mitochondria runs counter to an expectation in the field that such mutations should alter proteins at the synapses that connect neurons. However, mitochondria are essential for the function of energy-hungry synapses—so these models may not conflict.

It was also surprising that the 3q29 cells had poorly functioning mitochondria because only one of the 22 genes deleted seemed to encode a protein found in mitochondria. However, the researchers said that this gene or another in the interval may instead regulate the production or import of mitochondrial proteins.

Mitochondria, found in every cell, produce energy from sugar or fat. Sometimes this process is aerobic (done with extra oxygen from inhaled air) and sometimes anaerobic (done without oxygen).

As a result of altered mitochondrial function, 3q29 cells lack metabolic flexibility, which means that mitochondria have difficulty adapting to changes in energy sources. This may interfere with neuronal development because mature neurons need to switch to relying on aerobic energy production during their differentiation.

The results show how 3q29 deletion affects the whole body, not just the brain: effects on mitochondria are seen in kidney cells as well as in brain cells. Individuals with 3q29 deletion syndrome also tend to be leaner, possibly due to altered fat metabolism.

“Ultimately, we want to understand which cellular changes like these are associated with specific clinical outcomes, which can help design more effective treatment strategies,” Purcell said.