Researchers have discovered how the gene variant DISC1, which is linked to schizophrenia and other psychiatric disorders, impairs a particular signalling pathway in neurons that is crucial for normal brain development. Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory, and colleagues, write about their findings in the 17 November issue of the journal Neuron.
DISC1, short for Disrupted in Schizophrenia-1, was first identified in a large Scottish family with high rates of schizophrenia, bipolar disorder and depression, and more recent studies have shown that the mutation can lead to changes in brain structure and impaired cognitive function. But exactly how it did this remained somewhat unclear.
For their study, Tsai and colleagues screened the genes of 750 participants. Some of the participants were healthy and some had psychiatric diseases. They found several common variants of DISC1, but it was clear that although these impaired brain development, they were not sufficient to cause psychiatric disease.
Tsai told the media that many people carry these mutations, and they probably have some defects in their brain development as a result:
“However, it’s also pretty clear that that by itself it is not sufficient to cause psychiatric disorder. That’s very consistent with the notion that there probably has to be a combination of several different genetic variations to trigger a clinically measurable outcome.”
In previous research, Tsai and the team found that DISC1 controls a cell signalling pathway called Wnt, which stimulates stem cell proliferation during the embryonic stage. This pathway also promotes the proliferation of neuroprogenitor cells, immature cells that eventually become neurons, and it is this function that is interesting in terms of psychiatric disease development.
Tsai explained in that study they found DISC1 actually maintains the integrity of the Wnt signalling, so any variant of DISC1 that undermines it is going to affect the proliferation of neuroprogenitors, with a knock-on effect on brain development. DISC1 keeps the pathway working by shutting off an enzyme called Gsk3-beta.
It is interesting that lithium, a common treatment for bipolar disease, targets Gsk3-beta.
So, building on the results of that study, for this study the team decided to investigate the possibility that DISC1 behaves like the body’s natural equivalent of lithium, “endogenous lithium”, to keep the Wnt signal working.
When the researchers found the DISC1 variants in the participants, half of whom were healthy and half of whom had schizophrenia or bipolar disorder, none of the single mutations was significantly more prevalent in the participants with psychiatric diseases than in the healthy participants.
Tsai said this suggests that in humans, the DISC1 variants on their own are not enough to cause disease.
So they experimented further. They selected four of the most prevalent DISC1 variants (A83V, R264Q, and L607F and S704C) and tested them in mice, zebrafish and human cells.
They found that three (A83V, R264Q, and L607F, but not S704C) of the four variants they tested did indeed disrupt the Wnt signalling. But, these were also the variants present in healthy people to the same extent, so again, that alone cannot be the sole route to disease.
The fourth variant, the one that did not disrupt Wnt signalling, did however do something else that was interesting: it appeared to stop neurons being able to move the right locations during key stages in brain development, when they need to link up with other cells.
Albert Wong, an associate professor of pharmacology at the University of Toronto was not involved in the study. He told the media that these findings are “an important step forward” in helping us understand how DISC1 variants affect the development of brain structure and function.
“This paper by Tsai’s lab makes the crucial link between disease-associated human DISC1 variants and Wnt/Gsk3-beta signaling and brain development,” said Wong.
Tsai said it is hardly surprising that given all this disruption at the cellular level, it still does not necessarily lead to disease:
“The brain is really a remarkable organ. It’s just so plastic and has this enormous capacity to compensate for any kinds of defects.”
She looks forward to future studies revealing further variants that might be involved in the development of schizophrenia and other psychiatric disorders.
As well as looking at the genetic factors, Tsai and colleagues write in their Neuron that they investigated the biochemistry of the Wnt signalling pathway, comparing healthy participants with those with bipolar disease. They found the signalling was much weaker in those with bipolar disease, suggesting it may share some of the same origins as schizophrenia: not just in terms of gene variants, but also in terms of the biochemistry, said Tsai.
Written by Catharine Paddock PhD