Gene Pathway Linked to Development of Schizophrenia

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In an award-winning study, researchers from The University of Texas Health Science Center at Houston (UTHealth) discovered a gene signaling pathway linked to a higher risk for developing schizophrenia by observing human-induced pluripotent stem cells created from blood samples of a single family. The pathway, phosphoinositide 3-kinase/glycogen synthase kinase 3 (PI3K/GSK3), contains differentially expressed genes, including serum-glucocorticoid kinase 1 (SGK1). This is an inhibitor of GSK3 beta and has been associated with schizophrenia.¹

“We believe this has direct implications for the treatment of patients,” senior author Consuelo Walss-Bass, PhD, MD, said to the press. “There is a new antipsychotic that just received approval from the Food and Drug Administration that directly targets the pathway we identified as dysregulated in neurons from the patients, and several other antipsychotics also target this pathway. This could help pinpoint who may respond better to treatments.”²

Walss-Bass, the first author, and postdoctoral research fellow Laura Stertz, PhD, took blood samples from members of a large Costa Rican family with multiple individuals with schizophrenia. The blood cells were changed into stem cells using human-induced pluripotent stem cell (hiPSC) technology. These cells were then redirected to become brain neurons. This allowed them to be studied in a virtual biopsy and compared to neurons from family members who did not have schizophrenia.

In the biopsies, researchers saw 5 schizophrenia candidate genes previously identified by genome association studies. Alterations caused by gene SGK1, which inhibits GSK3 activity, are linked to whether a person has a higher risk of schizophrenia.

Walss-Bass had this to say on the discovery: “Mental health research has lagged behind because we don't know what is happening biologically. We are diagnosing people based on what they are telling us. Even postmortem, the brain tissue in mental health disorders looks perfectly fine. In Alzheimer disease, you can see a difference compared to controls. But not in psychiatric disorders. Now by studying virtual brain biopsies, we can tell what is happening biologically.”²

Walss-Bass also said that identifying patients with specific biological pathway markers could identify them as the best candidates for medications. This pre-emptive, personal pharmacology may be what is needed to best treat psychiatric disorders.

“We were able to find significant, meaningful differences with a small control group,” Walss-Bass said. “Neurons of patients with schizophrenia had alterations in the signaling pathway. This research may help to understand how or why some antipsychotics targeting GSK3 work and also to develop other target-specific medications.”²

References

1. Stertz L, Di Re J, Pei G, Fries G, et al. Convergent genomic and pharmacological evidence of PI3K/GSK3 signaling alterations in neurons from schizophrenia patients. Neuropsychopharmacol. 2020;46:673–682.

2. University of Texas Health Science Center at Houston. Gene pathway linked to schizophrenia identified through stem cell engineering. News release. Science Daily. December 21, 2020. https://www.sciencedaily.com/releases/2020/12/201221134136.htm