By delving into the genetic risk factors, researchers from Rutgers University and Emory University are unravelling the mechanisms through which schizophrenia presents itself. Their focus on the most potent recognized genetic risk factor for the condition provides valuable insights into the disease’s manifestation.
The risk of schizophrenia surges by almost 40 times due to the absence of a small segment on chromosome 3, referred to as 3q29 deletion syndrome. Through the examination of two distinct models of this syndrome—engineered mice with the deletion using CRISPR and human brain organoids—researchers have scrutinized the shared patterns of modified gene behavior. These systems have unveiled compromised mitochondrial function, potentially leading to energy deficits in the brain that contribute to psychiatric symptoms and disorders.
“Our findings provide robust evidence supporting the notion that mitochondrial dysregulation plays a role in the emergence of schizophrenia,” stated Jennifer Mulle, co-senior author of the study and associate professor of psychiatry, neuroscience, and cell biology at Rutgers Robert Wood Johnson Medical School. The intricate relationship between mitochondrial dynamics and neuronal maturation warrants further comprehensive investigation,” she added. The study was published in Science Advances.
In 2010, Mulle, a member of Rutgers’ Center for Advanced Biotechnology and Medicine, along with colleagues, initially demonstrated the link between 3q29 deletion and the risk of schizophrenia. These findings align with research on another genetic risk factor for schizophrenia, 22q11 deletion syndrome (DiGeorge syndrome), which also involves disturbances in mitochondrial function.
Ryan Purcell, co-lead author of the study and assistant professor of cell biology at Emory University School of Medicine, emphasized the importance of comprehending the fundamental cellular pathology behind genetic variants associated with schizophrenia. “This insight provides a foundation that could potentially help untangle the intricate polygenic nature of schizophrenia and enhance our understanding of its neurobiology,” Purcell said.
While approximately one in 30,000 individuals are born with 3q29 deletion syndrome, which elevates the risk of schizophrenia, it can also lead to intellectual disability, autism spectrum disorder, and congenital heart defects. The influence of 3q29 deletion on schizophrenia susceptibility surpasses that of any known single gene variant, yet the specific contributions of individual genes within the deletion remain an ongoing area of exploration.
Contrary to the prevailing assumption that mutations in synaptic proteins contribute to schizophrenia, the discovery that various chromosomal deletions associated with the condition affect mitochondria functions offers a novel perspective. Despite the focus on synaptic alterations, mitochondria are essential for sustaining energy-demanding synapses, potentially reconciling these seemingly opposing models.
Interestingly, the impaired mitochondrial function observed in 3q29 cells was unexpected, given that only one of the deleted genes within the 3q29 interval appears to encode a mitochondrial protein. However, the researchers speculate that this gene, or others within the region, might regulate the synthesis or transportation of mitochondrial proteins, contributing to the dysfunction.
Mitochondria, ubiquitous in cells, play a pivotal role in generating energy from sugar or fat through aerobic or anaerobic processes. Altered mitochondrial function in 3q29 cells leads to a deficiency in metabolic adaptability, preventing efficient adjustments to varying energy sources. This disruption may hinder the development of neurons, which necessitates a transition to aerobic energy production during maturation.
The study’s implications extend beyond the brain, revealing that the effects on mitochondria extend to kidney cells, demonstrating a systemic impact of 3q29 deletion. Individuals with 3q29 deletion syndrome often exhibit smaller stature, potentially linked to altered fat metabolism.
“Ultimately, our goal is to link these cellular changes to specific clinical outcomes, offering insights that could enhance the effectiveness of therapeutic approaches,” highlighted Ryan Purcell.
