GHENT, Belgium—Researchers from Belgium have linked an incorrectly cleaved protein to the development of schizophrenia, a finding they hope will lead to improved diagnosis and treatment of schizophrenia and related psychiatric disorders.
In a study published July 14 in the Proceedings of the National Academy of Sciences (PNAS) online edition, scientists from the Flanders Interuniversity Institute for Biotechnology (VIB) describe how the Nrg-1 protein—an essential factor in the development and proper function of the brain and nervous system—becomes disturbed.
Until now, no clear cause of schizophrenia has been found, but scientific studies have suggested that faulty functioning of the Nrg-1 protein plays a role. Nrg-1 can carry out its function properly only when it has been cleaved in a specific way; improper cleavage can lead to behavioral disturbances. The Flemish scientists showed that Nrg-1 is cleaved by gamma-secretase in cells, and that its cleavage is impaired in the areas where Aph1BC-gamma-secretase is strongly expressed—the cerebral cortex, hippocampus and cerebellum—but not in the striatum, where expression is low.
"On the one hand, these results strengthen the case for the involvement of Nrg-1 signall-ing in the pathogenesis of schizophrenia, a topic that has been of strong interest over the last three years," says the study's lead co-author Bart DeStrooper. "On the other hand, this paper is the first to implicate the need for gamma-secretase cleavage of Nrg-1 in normal brain function. Or in other words, that insufficient production of and signaling by the Nrg1 intracellular fragment can lead to schizophrenia-like symptoms."
The scientists set out to describe the consequences of the deficiency of a specific subset of gamma-secretase complexes, the Aph1B/C-containing gamma-secretase complexes. Specifically, the scientists demonstrated that the Aph1B/C-gamma-secretase complex is expressed in brain areas relevant to schizophrenia pathogenesis and that Aph1B/C deficiency causes pharmacological and behavioral abnormalities that can be reversed by antipsychotic drugs. At the molecular level, the scientists found accumulation of Nrg-1 fragments in the brain of Aph1BC −/− mice. The scientists further demonstrated that a Val-to-Leu mutation in the Nrg1 transmembrane domain, associated with increased risk for schizophrenia, affects gamma-secretase cleavage of Nrg-1.
This finding suggests that dysregulation of Nrg-1 could increase risk for schizophrenia and related disorders, but further research is needed to examine the in vivo consequences of disrupting Nrg-1 back signaling, DeStrooper says.
"If Nrg-1 back signaling turns out to be important in avoiding schizophrenia or related diseases, one might try to enhance/modulate gamma-secretase cleavage of Nrg-1," he says. "Increasing gamma-secretase activity seems however a problematic strategy: firstly, there is up to now no clear way to do this; secondly, increased gamma-secretase activity might result in increased Abeta production, and therefore, increased risk for Alzheimer's disease."
The study, Deficiency of Aph1B/C-γ-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment, was funded by a Methusalem grant from the Flemish government and a European Union MEMOSAD grant.