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HomeLifestyleHealthHow Schizophrenia genetic risk factor weakens mitochondrial function: Study | Health

How Schizophrenia genetic risk factor weakens mitochondrial function: Study | Health

By examining the strongest known genetic risk factor for schizophrenia, scientists at Rutgers University and Emory University are learning more about how the disease manifests.

How Schizophrenia genetic risk factor weakens mitochondrial function: Study(Shutterstock)
How Schizophrenia genetic risk factor weakens mitochondrial function: Study(Shutterstock)

The risk of schizophrenia is increased by nearly 40 times when a tiny piece of chromosome 3 is missing, a condition known as 3q29 deletion syndrome. In two different models of the 3q29 deletion syndrome, including mice with the deletion generated using CRIPSR and human brain organoids, or three-dimensional tissue cultures used to investigate disease, researchers have now analysed overlapping patterns of altered gene activity. Both of these systems show deteriorated mitochondrial activity. Due to this dysfunction, the brain may experience energy shortages that manifest as psychiatric symptoms and diseases.

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“Our data give strong support to the hypothesis that mitochondrial dysregulation is a contributor to the development of schizophrenia,” said Jennifer Mulle, associate professor of psychiatry, neuroscience and cell biology at Rutgers Robert Wood Johnson Medical School and a co-senior author of the study published in Science Advances. “The interplay between mitochondrial dynamics and neuronal maturation is an important area for additional detailed and rigorous study.”

Mulle, a member of the Center for Advanced Biotechnology and Medicine at Rutgers, and colleagues first showed that 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 has also been found to involve disrupted mitochondrial function.

“For genetic variants associated with schizophrenia, we want to understand the primary 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 schizophrenia’s polygenic complexity and better understand the neurobiology.”

About one in 30,000 people are born with 3q29 deletion syndrome. In addition to increasing the risk for schizophrenia, 3q29 deletion can include intellectual disability, autism spectrum disorder and congenital heart defects. The effect of 3q29 deletion on schizophrenia risk is more than any single known gene variant, but the contributions of individual genes within the deletion are still being unraveled.

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

It was also surprising that 3q29 cells have poorly functioning mitochondria because only one of the 22 genes in the deletion appears to encode a protein located in mitochondria. However, that gene or others within the interval may instead regulate the production or importation of mitochondrial proteins, the researchers said.

Mitochondria, which are 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, meaning their mitochondria have difficulty adapting to changes in sources of energy. This may interfere with neuronal development because maturing neurons need to switch to relying on aerobic energy production as they differentiate.

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

“Eventually, we want to understand which cellular changes like these are linked to specific clinical outcomes, which could help in designing more effective therapeutic strategies,” Purcell said.

This story has been published from a wire agency feed without modifications to the text. Only the headline has been changed.

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