From Science Daily – Nov. 17th 2011. In recent years, scientists have found several genetic mutations associated with an increased risk of psychiatric illness such as schizophrenia and bipolar disorder. One mutation, called DISC1 – an abbreviation of “Disruption in Schizophrenia-1″ – was first identified in a large Scottish family with high rates of schizophrenia, bipolar disorder and depression.
Studies have since shown that DISC1 mutations may lead to altered brain structure and cognitive impairment, but it is unknown exactly how this happens. A new study by Li-Huei Tsai, director of the MIT Picower Institute for Learning and Memory, shows that DISC1 mutations compromise a specific signaling pathway in neurons is critical for normal brain development.
In a genetic screen of 750 people – some of whom were healthy and some of which psychiatric illness – researchers found several common variants of the DISC1 gene. However, despite these mutations disrupts the normal development of the brain that were not necessarily enough to cause disease on its own.
“Much of the human population can lead to this [genetic defect], and is likely to actually have some defects in brain development. However, it is also quite clear that that in itself is not sufficient to cause psychiatric disorder” Tsai says. “That’s very consistent with the idea that probably has to be a combination of several different genetic changes to cause clinically measurable results.”
The study was published in the November 17 edition of the journal Neuron. Author of the paper is Karun Singh, a postdoctoral researcher at the Picower Institute.
Arrested development
In a study published in 2009, Tsai and colleagues showed that the gene DISC1 regulates a signaling pathway known as Wnt. This pathway has been found to stimulate proliferation of stem cells during embryonic development. The most important thing in terms of psychiatric illness, Wnt signaling promotes cell proliferation neuroprogenitor, immature cells that eventually become neurons.
“What we found is that DISC1 actually maintains the integrity of Wnt signaling,” says Tsai. “So if DISC1, for any reason, you lose, then Wnt signaling is impaired. This also resulted in the proliferation and development neuroprogenitor deterioration of the brain.”
Tsai and colleagues showed that DISC1 regulates Wnt signaling by cutting an enzyme called GSK3-beta. (Note that GSK3-beta is also the target of lithium, a common treatment for bipolar disorder.) “We have proposed in that document is basically endogenous DISC1 lithium, to maintain the integrity of Wnt signaling,” says Tsai.
In the new role of the neuron, Tsai’s lab investigated the impact of DISC1 mutations in the human population. Together with researchers at the Stanley Center for Psychiatric Research at the Broad Institute, sequenced the DISC1 gene in more than 700 people – half of them had schizophrenia or bipolar disorder, the rest were healthy – and identified several variants of the DISC1 gene.
However, none of these individual mutations were significantly more frequently among healthy people sick. “That suggests that DISC1 variants in humans alone do not cause disease,” says Tsai.
The researchers chose four of the most common DISC1 mutations and tested their effects in mice, zebrafish and human cells. It turned out that three of these variants result in impaired Wnt signaling. However, some of these mutations were found in healthy people, so they are not sufficient to cause disease on its own.
The fourth variant does not affect Wnt signaling, but affected the ability of neurons “to go to the correct position during brain development and how circuits with other cells.
Albert Wong, associate professor of pharmacology at the University of Toronto, says the findings represent “an important step forward” in understanding how DISC1 mutations may lead to abnormal brain structure and function. “This Tsai laboratory work makes the crucial link between human-associated diseases Wnt/Gsk3-beta DISC1 variants and signaling and brain development,” says Wong, who was not involved in this research.
“A remarkable organ”
Tsai says it is not surprising that despite the clearly genetic defects cause a malfunction at the cellular level, which does not always lead to disease. “The brain is actually a remarkable organ. It is so plastic and has this tremendous capacity to compensate for any defects,” he says.
It is hoped that future studies will reveal other genetic mutations that are also necessary to produce schizophrenia and other psychiatric disorders.
In the document of Neuron, the researchers also examined the levels of Wnt signaling in people with bipolar disorder and found they were much lower than in healthy individuals, suggesting that bipolar illness and schizophrenia may share some of the same origins. “A large number of genes involved in schizophrenia are also implicated in bipolar disorder. Now, biochemistry, seems to be the case too,” says Tsai.
