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Schizophrenia genetic risk factor weakens mitochondrial function: Study

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Washington | August 20, 2023 7:45:45 PM IST
Researchers have investigated overlapping patterns of altered gene activity in two separate models of the 3q29 deletion syndrome, including human brain organoids and mice with the deletion produced via CRIPSR. Mitochondrial activity has declined in each of these systems.

When a small portion of chromosome 3 is missing, a disease known as 3q29 deletion syndrome results, which increases the risk of schizophrenia by roughly 40 times. This dysfunction may lead to energy shortages in the brain, which can cause psychiatric symptoms and disorders.

Our data give strong support to the hypothesis that mitochondrial dysregulation is a contributor to the development ofschizophrenia, saidJennifer Mulle, associate professor of psychiatry, neuroscience and cell biology atRutgers Robert Wood Johnson Medical Schooland a co-senior author of the study published inScience Advances. The interplay between mitochondrial dynamics and neuronal maturation is an important area for additional detailed and rigorous study.

Mulle, a member of theCenter for Advanced Biotechnology and Medicineat Rutgers, and colleagues first showed that 3q29 deletion was a risk factor forschizophreniain 2010. The findings converge with work on another genetic risk factor forschizophrenia, 22q11 deletion syndrome (or DiGeorge syndrome), which has also been found to involve disruptedmitochondrial function.

For genetic variants associated withschizophrenia, 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 throughschizophrenias 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 unravelled.

The finding that variousschizophrenia-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 ofaltered 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. (ANI)

 
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