Evidence Linking DISC1 Gene to Mental Illness Builds

meaning that several genes, as well as environmental factors, contribute to their development. That’s why the Scottish family proved to be such a boon. The 1990 study, which was conducted by a team including David St. Clair, Douglas Blackwood, and Walter Muir of the University of Edinburgh, U.K., suggested that the region disrupted by the translocation seen in affected members of the Scottish family held one or more genes involved in the disorders. The gene search went slowly at first, but in 2000, a team led by David Porteous and Kirsty Millar, also at Edinburgh, identified two previously unknown genes on chromo- some 1 that were interrupted by the genetic anomaly. Attention has focused on the first, DISC1, which normally produces a large pro- BEHAVIORAL GENETICS tein the structure of which suggests that it interacts with other proteins. Shortly after identification of DISC1, a Evidence Linking DISC1 Gene to follow-up study by the Edinburgh workers buttressed a causative role for the gene in the Mental Illness Builds mental disorders of the Scottish family; that linkage analysis had a high degree of sta- Animal studies add weight to the view that an important gene for brain development tistical validity—a LOD score of 7 when 3 is on December 28, 2007 plays a role in diseases such as schizophrenia and depression considered good. In this family, “we’re as close to causality as you could get,” Porteous Every clan has its misfits, but an extended think this gene is really the first big break- says. Even so, environmental influences may family in northern Scotland is extraordinary. through in schizophrenia … and other men- still be important, as a few members carry the More than half have suffered from schizo- tal diseases,” says Christopher Ross of Johns translocation but remain unaffected. phrenia or some other form of mental illness. Hopkins University School of Medicine in The Scottish family is unusual because so A group of Scottish researchers reported in Baltimore, Maryland. many members develop bipolar disorder and 1990 that the affected people all carried the After decades of following false leads, depression, as well as schizophrenia, and no www.sciencemag.org same genetic anomaly—a translocation, or researchers are cautiously optimistic that they one has detected a similar DISC1 abnormality swap, of two stretches of DNA on the long are on the right track with DISC1. But the evi- in other families. In 2003, however, Leena arms of chromosomes 1 and 11. With mod- dence isn’t airtight. Except Peltonen of the National esty, the investigators wrote that this “may be in the Scottish family, Public Health Institute in , 12 (2005) a promising area to examine” for genes that researchers haven’t consis- Helsinki, Finland, and her 7 predispose people to mental illness. tently linked any particular colleagues reported a link- The area turned out to be very promising DISC1 variant to a mental age between a particular set indeed. By the year 2000, it had led disease. “There’s no smok- of three single-nucleotide Downloaded from researchers to a gene called DISC1, which ing gun,” cautions psychia- variants (single-nucleotide may be a key player in the chain of events trist Daniel Weinberger of polymorphisms) in DISC1 leading to mental illness. The circumstantial the National Institute of and schizophrenia in a evidence for assigning a major role to Mental Health in Bethesda, group of 458 Finnish fami- CELL BIOLOGY ET AL., NATURE DISC1 (Disrupted-in-Schizophrenia 1) is Maryland. But if the connec- lies. “This is the first genetic strong. Several studies have linked the gene tion of DISC1 to mental dis- evidence that DISC1 has to schizophrenia, major depression, bipolar orders holds up, it might lead something to do with disorder, and autism; recent findings on to better therapies for treat- the more common garden DISC1’s biological function appear to sup- ing the conditions—espe- variety of schizophrenia,” port the hypothesis. cially schizophrenia, a dev- Peltonen says. Animal studies have shown that the gene astating disease that is now Other workers have is needed for normal brain development poorly controlled at best. picked up linkages between both in the embryo and later in life and that DISC1 variants and schizo- blocking its function produces subtle abnor- The hunt begins Held in place. An RNAi that phrenia in a few U.S. and malities in brain structure resembling those Gene hunters have had a blocks DISC1 synthesis prevents European families. And this migration of neurons (green) to seen in patients with schizophrenia. The pro- hard time pinning down the the upper layer of the cortex in year, the Peltonen team tein encoded by the gene also turns out to be genes involved in mental mice (right micrographs); controls linked the gene to bipolar part of a nerve cell signaling pathway disorders mainly because are on the left. disorder and to autism in involved in learning, memory, and mood. “I the diseases are complex, their Finnish population. CREDITS (TOP TO BOTTOM): SPENCER JONES/GETTY IMAGES; KAMIYA 1062 16 NOVEMBER 2007 VOL 318 SCIENCE www.sciencemag.org Published by AAAS NEWSFOCUS Research on DISC1’s normal function has In these mice, the mutant DISC1 protein DISC1 inhibits this activity until rising cAMP strengthened the case that it is involved in exerted its effects in the embryos. Another concentrations cause it to drop off the PDE4B mental disease. For starters, the gene is Johns Hopkins group led by Hongjun Song molecule. Alterations in DISC1 structure that expressed in many tissues, but particularly in has traced the gene’s effects in the brains of disrupt the normal DISC1-PDE4B interaction brain areas such as the hippocampus and cere- adult mice. In these experiments, described might therefore interfere with learning and bral cortex that are affected in schizophrenia. in the 21 September issue of Cell, the memory, among other things. “This is very That puts the gene’s protein product in the researchers showed that inhibiting DISC1 important work,” Sawa says. “Memory and right locations to influence the development expression in newly formed adult brain neu- cognition are both disturbed in schizophrenia of the mental disease. rons produces effects opposite to those seen in and bipolar disease.” In addition, as predicted from DISC1’s the other mouse models. Neurite outgrowth Additional evidence that disrupting the structure, researchers have unmasked numer- increased rather than decreased, and neurons DISC1-PDE4B interaction can affect mental ous binding partners for the protein. The cur- migrated farther than normal. “If you disrupt states comes from work on mouse models rent count stands at about 50, Porteous says, DISC1 function, everything goes faster,” developed by Steven Clapcote and John including “10 or 12 where the interaction Song says. Roder of Mount Sinai Hospital in Toronto, influences function.” Several of these partners Sawa notes that there are precedents for the Canada, and their colleagues in collaboration suggest a role for DISC1 in brain development same molecule having opposite effects with the Porteous team. (The results appeared and cognition. depending on its context. Indeed, he is now on 3 May in Neuron.) By screening a library of For example, about 5 years ago, three inde- working with Song and Pletnikov to identify mutant mice at the RIKEN research institute pendent groups, those of Porteous, Akira Sawa the molecular change that can switch DISC1’s in Japan, the researchers identified two lines of Johns Hopkins University School of activity from inhibiting to stimulating neu- of mice, each with a different DISC1 mutation Medicine, and Christopher Austin at Merck ronal migration. But whatever the outcome, that reduces DISC1 binding to PDE4B. Research Laboratory in West Point, Pennsylva- Behavioral studies further showed that nia, found that DISC1 binds to a protein called mice with one mutation display symptoms NUDEL (for NudE-like) that is needed for the construed as schizophrenia-like, including neuronal migrations that occur during brain hyperactivity and impaired learning and development. Several other partners of DISC1, memory. Those symptoms were reduced by on December 28, 2007 including FEZ1, LIS1, dynein, and tubulin, are treatment with the drug rolipram, a PDE4B also involved in nerve-cell migrations. inhibitor, and also by treatment with two That suggests that brain development drugs used to treat human schizophrenia. The might go awry if DISC1’s function is altered other mouse strain, Porteous says, had more or missing. Evidence supporting that idea depression-like symptoms. For example, includes the demonstration about 3 years ago when placed in water, the animals quickly by the Sawa team that inhibiting DISC1 syn- gave up trying to escape and simply floated. thesis in mouse embryos with small interfer- These animals responded to treatment with www.sciencemag.org ing RNAs causes abnormal migration of neu- Brain disruption. Putting a mutant human DISC1 antidepressant drugs. Developing drugs to rons to the cerebral cortex. gene in mice produces enlarged lateral ventricles regulate an enzyme such as PDE4B might More evidence comes from animal models similar to those of human schizophrenia patients. lead to better ways of treating schizophrenia developed in the past year. This fall, two Johns and other mental disorders. Hopkins groups, one led by Sawa and the researchers have long thought that schizo- The fact that DISC1 associates with so other by Mikhail Pletnikov, published reports phrenia is the result of aberrant brain develop- many different proteins might help explain on two similar mouse models produced by ment, and the results with these models but- the diversity of conditions to which it has introducing a truncated version of the DISC1 tress the case that irregularities in DISC1 been linked.

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