Schizophrenic genes located
therapy targets.
The US National Institute for Mental Health estimates that 51m people suffer from schizophrenia worldwide. 80 per cent of these cases appear to be inherited, but the specific genetic components underlying the susceptibility of an individual has remained elusive. Progress has been made in recent years to find the genetic causality of the disease suggesting that mutations in the PPP3CC gene could contribute to increased susceptibility. The researchers from MIT and Japan studied genetically engineered mice and the genetic makeup of schizophrenia sufferers, to locate both the PPP3CC gene and genes in the early growth response (EGR) gene family as suspects for causing schizophrenia. These genes play a critical role in the calcineurin cascade, which is central to neuronal functions and whose disturbance would cause the disorganized thinking, attention deficits, memory and language problems that characterize schizophrenia Genetic analysis of the calcineurin-related genes in two sets of Japanese schizophrenia samples confirmed the association of the PPP3CC gene with onset of schizophrenia. These findings replicate previous association studies in 210 ethnically diverse triads from the US and 200 triads from South Africa. The study looked at a total of 84 single nucleotide polymorphisms (SNPs) in124 schizophrenia pedigrees consisting of 374 individuals and discovered that the EGR family genes (EGR2, EGR3 and EGR4) also exhibit significant association with schizophrenia. "These data suggest that the brain signals governed by calcineurin stand at a convergent point of the molecular disease pathology of schizophrenia, and the involvement of the EGR genes reinforces this," said Takeo Yoshikawa of the RIKEN Brain Science Institute and co-author of the article published in the latest edition of the 'Proceedings of National Academy of Science'. "This knowledge could lead to new schizophrenia therapeutics targeting the calcineurin system," he continued. A large body of pharmacological data suggests that alterations in the regulation of, or interactions between the dopamine and glutamate neurotransmitter systems may play important roles in schizophrenia. The expression of calcineurin is particularly enriched in the central nervous system (CNS) where it is positioned downstream of dopaminergic, glutamatergic signalling as well as being involved in the N-methyl-D-aspartic acid (NMDA) receptor-mediated synaptic plasticity, alterations of which are all observed in sufferers of schizophrenia. The calcineurin cascade could therefore provide a functional link between these two neurotransmitter systems and be crucial to the development of schizophrenia. The dorsolateral prefrontal cortex (DLPFC) has been linked to many of the negative symptoms of schizophrenia and the recent study shows that expression of EGR2 and EGR3 are decreased in this region of schizophrenic brains when compared to control patients. Curiously, the expression of PPP3CC was found to be no different in this brain area in sufferers and control subjects. A recent report in 'Biological Psychiatry' showed that PPP3CC mRNA levels were reduced in the hippocampus, a part of the brain located inside the temporal lobe, of schizophrenics. "This study provides genetic and biological evidence that PPP3CC and EGR3, both constituents of the calcineurin signalling pathway, may independently elicit increased risk for schizophrenia," said Susumu Tonegawa, Picower Professor of Biology and Neuroscience at MIT and co-author of the article. "These findings raised a novel and potentially important role for EGR genes in schizophrenia pathogenesis."
