Schizophrenia Research Forum - A Catalyst for Creative Thinking

Lis1 Acts as Middleman for Actin and Microtubules

23 December 2005. If association hints at guilt, then researchers might make a case that Lis1 has a hand in the pathology of schizophrenia. This protein is in cahoots with some suspect characters, including DISC1 (see Brandon et al. 2005) and Reelin (see Assadi et al., 2003). A mutation of the former, full name Disrupted-In-Schizophrenia 1, is already on trial for causing the disease in an extended Scottish family with a high prevalence of neuropsychiatric disorders (see Millar et al., 2001 and SRF related news story), while postmortems showed that reelin is suspiciously reduced in the brains of people with schizophrenia or bipolar disorder with psychosis, but not unipolar depression (see Guidotti et al., 2000). But lest there be a rush to condemn Lis1, wouldnít it be best to find out a little more about the protein? Elizabeth Ross and colleagues at Weill Medical College of Cornell University, New York, have done some detective work. Their findings, published online Dec 18 in Nature Neuroscience, suggest that Lis1 acts as the middleman between the cytoskeletal elements actin and microtubules. The data explain how the actin filaments interact with the tubulin cables to promote cell motility, a prerequisite for neuronal migration, as well as neuronal plasticity, two phenomena that are likely to be important in the pathology of schizophrenia and other disorders.

Lis1 was first identified because loss-of-function mutations in the gene cause a neurodevelopmental disease called lissencephaly (from the Greek, "lissos" meaning smooth and "enkephalos" meaning brain). In people born with this rare disease, neurons do not migrate properly and the cerebral cortex fails to fully develop, leaving a smooth cortical surface. Severe mental retardation, motor problems, and, often, death during infancy are the result. Researchers are currently trying to figure out why these mutations have such drastic consequences on cortical development. While it is known that Lis1 binds to microtubules, how this fits in with neuronal migration or lissencephaly has not been determined.

What has been clear for some time is that actin polymerization and depolymerization is a prerequisite for any cellular motility. Actin is the scaffold for the cytoskeleton, and for migration to take place, actin polymers must be disassembled at the trailing edge and reassembled at the leading edge of the moving cell. Ross and colleagues show that Lis1 promotes actin polymerization by stabilizing the active form of Cdc42, one of a number of small GTPases that regulate actin polymerization. When Cdc42 is turned on, it stimulates the enzyme that catalyzes the addition of actin monomers to growing actin chains, and so drives cell motility.

First author Stanislav Kholmanskikh and coworkers studied the role of Lis1 in migration of cerebellar granule cells. During their travels, these cells express the N-methyl-D-aspartate (NMDA) type of glutamate receptor (see Current Glutamate Hypothesis of schizophrenia by Moghaddam), and they can be persuaded to move on culture slides if given NMDA agonists such as glycine or serine. But the authors found that neurons from Lis1+/- mice responded poorly to serine, moving almost half as slowly as normal cells. They also found that extra Lis1 corrected this effect, but not if the cells also produced a dominant-negative form of Cdc42. In contrast, Lis1+/- cells producing a constitutively active form of Cdc42 migrated much faster than those without the GTPase. The results provided the researchers with the first solid evidence that Lis1-driven motility is related to activation of Cdc42.

The authors next investigated the activation process itself. One possibility was that it might involve another protein because active small GTPases are often protected by binding partners. In the leading edge of motile cell processes, for example, a protein called IQGAP stabilizes Cdc42. In fact, though IQGAP co-localizes with Cdc42/actin in growing neurites, Kholmanskikh and colleagues found that this is not the case in Lis+/- cellsóin other words, the full complement of Lis1 is necessary to get IQGAP and Cdc42 together. This is where the microtubule connection comes in. Researchers previously showed that IQGAP forms a complex with a microtubule binding protein called cytoplasmic linker protein 170 (CLIP-170). Curiously, Lis1 also binds to CLIP-170 (see Coquelle et al., 2002), suggesting that all these proteins, Cdc42, IQGAP, CLIP-170 and Lis1 may exist in some sort of complex. Kholmanskikh and colleagues confirmed this by immunoprecipitation experiments.

In sum, these findings show that Lis1 is key in converting extracellular signals to intracellular motility and suggest how Lis1 mutations could prevent the proper migration of neurons to the cerebral cortex in lissencephaly. As for schizophrenia, it seems that there is not sufficient evidence to prosecute that case, yet. It is curious, however, that Lis1 forms a complex with DISC-1 and a protein called NUDEL (a.k.a., Ndel1). The genetic translocation in the DISC1 gene that is linked to schizophrenia produces DISC1 protein that cannot bind NUDEL, not to mention neuronal cells that cannot form neurites (see Ozeki et al., 2003). This latter observation is particularly intriguing because just like cell motility, neurite formation is dependent on rearrangement of the actin cytoskeleton.–Tom Fagan

Kholmanskikh SS, Koeller HB, Wynshaw-Boris A, Gomez T, Letourneau PC, Ross ME. Calcium-dependent interaction of Lis1 with IQGAP1 and Cdc42 promotes neuronal motility. Nat Neurosci. 2005 Dec 20. Abstract

Comments on News and Primary Papers

Primary Papers: Calcium-dependent interaction of Lis1 with IQGAP1 and Cdc42 promotes neuronal motility.

Comment by:  Shinji Hirotsune
Submitted 22 December 2005
Posted 22 December 2005

Lissencephaly is characterized by smooth cerebral surface, thick cortex, and dilated lateral ventricles due to incomplete neuronal migration. Lis1 is one of the major mutated genes linked to this disease. Recent reports support Lis1 as an important regulator of cytoplasmic dynein heavy chain and microtubule organization with Ndel1, which is a binding partner of Lis1.

For neuronal migration, proper regulation of the cytoskeleton including microtubules and actin filaments is also essential (reviewed by Luo, 2000 and Noritake et al., 2005). Although accumulating evidence suggested the presence of a cross-talk mechanism between these two cytoskeletal elements, the precise mechanism remained to be elucidated. The paper from Rossís group has shed light on this important paradigm. They demonstrated that Lis1 is a key molecule which promotes Cdc42 activation through interaction with the calcium-sensitive GTPase scaffolding protein IQGAP1 and perimembrane localization of IQGAP1 and CLIP170, thereby tethering microtubule ends to the cortical actin filaments.

The regulatory machinery of the cytoskeleton is also essential for the formation of highly specialized presynaptic terminals and postsynaptic structure and the clustering of neurotransmitter receptors. In fact, Lis1-disrupted mice displayed learning and memory impairment. Rossís paper will become a great milestone in linking the regulation of brain morphogenesis and specialized neuron function.

Luo L. Rho GTPases in neuronal morphogenesis. Nat Rev Neurosci. 2000 Dec;1(3):173-80. Review. Abstract

Noritake J, Watanabe T, Sato K, Wang S, Kaibuchi K. IQGAP1: a key regulator of adhesion and migration. J Cell Sci. 2005 May 15;118(Pt 10):2085-92. Review. Abstract

View all comments by Shinji Hirotsune

Primary Papers: Calcium-dependent interaction of Lis1 with IQGAP1 and Cdc42 promotes neuronal motility.

Comment by:  Nick Brandon (Disclosure)
Submitted 28 December 2005
Posted 28 December 2005

Lis1 is known to play a crucial role in neuronal migration and neurogenesis. This is shown most dramatically by human lissencephaly where mutations in Lis1 give rise to a reduction in the convolutions of the cerebral cortex and disrupted cortical layering (Dobyns, 1989). This current paper builds on earlier work showing that the neuronal migration deficits in Lis1+/- animals is due in part to dysregulation of small GTPases such as Cdc42 and rac1 and consequent disruption of the actin cytoskeleton. The new manuscript details the molecular mechanism for the observed deficiency by revealing that Lis1 activates small GTPases through interacting with a GTPase scaffolding protein known as IQGAP1 in a calcium-dependent manner. Understanding the normal function of Lis1 could be important to allow us to understand the root causes of not only lissencephaly but also other diseases with common deficits. This includes schizophrenia, where postmortem studies show that schizophrenics have neuroanatomical pathologies which include abnormal neuronal migration and orientation (see Harrison and Weinberger, 2004, for review and further references). The paper reveals how NMDA receptor activation can promote neuronal migration through Lis1-mediated regulation of the cytoskeleton. "Glutamatergic hypofunction" centered around the NMDA-R is a very hot topic for schizophrenia causation at the moment, so this paper could also provide more information for this theory (Coyle and Tsai, 2004).

Our lab takes a keen interest in developments in the understanding of Lis1 due to the link to schizophrenia. Our particular interest is through DISC1, a schizophrenia risk gene for which strong genetic and biological data is accumulating at the moment to support a role in the disease process. A second link is through the reelin signaling pathway, which has been shown to interact physically and genetically with Lis1 (Assadi et al., 2003). Reelin is a molecule which has been implicated in schizophrenia with Reelin+/- mice also showing cortical layering deficits.

In an early paper from our own group we showed that DISC1 binds Lis1 (Brandon et al., 2004). This observation has been confirmed and functionally dissected in a beautiful study from Akira Sawa's group (Kamiya et al., 2005; see also SRF related news story). This study shows that DISC1 is a critical component of a Lis1-Nudel-Dynein protein complex at the centrosome. Expression of a mutant form of DISC1 is shown to disassociate Lis1 and other proteins from the centrosome and lead to abnormal development of the cerebral cortex in vivo. Reductions in DISC1 expression were also shown to cause abnormalities in cerebral cortex formation. Thinking about the current paper on Lis1, we do not know the role, if any, of small GTPases in DISC1 function. Our group has recently obtained a detailed protein-protein interaction network around DISC1, and within the network there are a number of links to GTPase regulatory proteins (Camargo et al., submitted). More specifically, at the recent Society for Neuroscience meeting, a poster from the Sawa lab showed that DISC1 binds to Kalirin-7, a guanine nucleotide exchange factor, and they showed evidence that DISC1 modulated the GEF function of Kalirin-7 on Rac-1 (Takaki et al., 2005). Exploring the connection between DISC1 and regulation of the actin cytoskeleton is clearly a priority.

Finally, Lis1 has always intrigued us, as it is also a regulatory subunit of platelet-activating factor acetylhydrolase (PAFAH), which degrades platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine), a biologically active lipid mediator. PAF has been implicated in the regulation of the NMDA-R with clear implications for schizophrenia through this system. Mutations within Lis1 which are thought to disrupt its binding to dynein complexes are also at the site of interaction with the subunits of PAFAH (Tarricone et al., 2004), so it is clearly important to consider the role of Lis1 in its guise as a component of PAFAH when neuronal migration deficits are considered. PAF-R knockout mice do have deficits in neuronal migration (Tokuoka et al., 2003), plus there is weak evidence for association between PAFAH and schizophrenia (Ohtsuki et al., 2002). Itís an exciting field which is providing interesting and complex answers.

Assadi AH, Zhang G, Beffert U, McNeil RS, Renfro AL, Niu S, Quattrocchi CC, Antalffy BA, Sheldon M, Armstrong DD, Wynshaw-Boris A, Herz J, D'Arcangelo G, Clark GD. Interaction of reelin signaling and Lis1 in brain development. Nat Genet. 2003 Nov;35(3):270-6. Epub 2003 Oct 26. Abstract

Brandon NJ, Handford EJ, Schurov I, Rain JC, Pelling M, Duran-Jimeniz B, Camargo LM, Oliver KR, Beher D, Shearman MS, Whiting PJ. Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders. Mol Cell Neurosci. 2004 Jan;25(1):42-55. Abstract

Coyle JT and Tsai G. NMDA receptor function, neuroplasticity, and the pathophysiology of schizophrenia. Int Rev Neurobiol. 2004;59:491-515. Abstract

Dobyns WB. The neurogenetics of lissencephaly. Neurol Clin. 1989 Feb;7(1):89-105. Abstract

Harrison PJ and Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry. 2005 Jan;10(1):40-68. Abstract

Kamiya A, Kubo K, Tomoda T, Takaki M, Youn R, Ozeki Y, Sawamura N, Park U, Kudo C, Okawa M, Ross CA, Hatten ME, Nakajima K, Sawa A. A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol. 2005 Dec;7(12):1067-78. Abstract

Ohtsuki T, Watanabe H, Toru M, Arinami T. Lack of evidence for associations between plasma platelet-activating factor acetylhydrolase deficiency and schizophrenia. Psychiatry Res. 2002 Jan 31;109(1):93-6. Abstract

Takaki M, Paek M, Kamiya A, Balkissoon R, Tomoda T, Penzes P and Sawa. A Disrupted in Schizophrenia-1 (DISC1) Binds to Kalirin-7 and Modulates Its Function as a GDP/GEP Exchange Factor. Program No. 674.9. 2005 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, 2005. Online.

Tarricone C, Perrina F, Monzani S, Massimiliano L, Kim MH, Derewenda ZS, Knapp S, Tsai LH, Musacchio A. Coupling PAF signaling to dynein regulation: structure of LIS1 in complex with PAF-acetylhydrolase. Neuron. 2004 Dec 2;44(5):809-21. Abstract

Tokuoka SM, Ishii S, Kawamura N, Satoh M, Shimada A, Sasaki S, Hirotsune S, Wynshaw-Boris A, Shimizu T. Involvement of platelet-activating factor and LIS1 in neuronal migration. Eur J Neurosci. 2003 Aug;18(3):563-70. Abstract

View all comments by Nick Brandon

Primary Papers: Calcium-dependent interaction of Lis1 with IQGAP1 and Cdc42 promotes neuronal motility.

Comment by:  Barbara K. Lipska
Submitted 28 December 2005
Posted 28 December 2005

Subtle abnormalities in cortical axon growth, and synapse formation have been long posited in schizophrenia, although the mechanisms of these deficits are still unclear (Lewis et al., 2003). Recently, with the growing evidence for a number of putative susceptibility genes, it was speculated that the genes may all converge functionally upon schizophrenia risk via an influence upon synaptic plasticity and the development and stabilization of cortical microcircuitry (Harrison and Weinberger, 2005).

The paper by Kholmanskikh and colleagues provides strong evidence that Lis1 is the transduction molecule linking extracellular Ca2+ activated motility signals with intracellular regulation of the cytoskeleton. Insufficient Lis1 destabilizes actin/microtubule complexes and thus disrupts cell architecture and neurite outgrowth. In other words, this paper provides data that Lis1, based on its biological role, might be a potential culprit in abnormal cortical development reported in schizophrenia. Lis1 has also been a suspect based on its association with DISC1, another neurodevelopmentally important molecule involved in cell architecture, mitochondrial transport, and synaptic development and plasticity.

DISC1 has been identified as a schizophrenia susceptibility gene based on linkage and SNP association studies and clinical data suggesting that risk polymorphisms impact on hippocampal structure and function (Millar et al., 2001; Blackwood et al., 2001; Devon et al., 2001; Ekelund et al., 2001 and 2004; Hennah et al., 2003; Hodgkinson et al., 2004; Callicott et al., 2005). In cell and animal models, C-terminus-truncated DISC1 disrupts intracellular transport, neural architecture, and migration, perhaps because it fails to interact with binding partners involved in neuronal differentiation, such as Nudel, FEZ1, and Lis1 (Ozeki et al., 2003; Brandon, 2004).

In our laboratory at the Clinical Brain Disorders Branch of the NIMH, we have investigated the expression of DISC1 and several of its binding partners in the postmortem human hippocampus and dorsolateral prefrontal cortex and explored their association with schizophrenia and with disease-associated DISC1 polymorphisms (Lipska et al., 2005). We hypothesized that variations in the DISC1 gene shown to be associated with schizophrenia would impact on the molecular phenotype of a DISC1 pathway in brain regions implicated in the disease. We found that the expression of Nudel, FEZ1, and Lis1 was significantly reduced in the hippocampus and prefrontal cortex of patients with schizophrenia and associated with high-risk DISC1 polymorphisms. Our results suggest that a putative abnormality in DISC1 biology in individuals carrying high-risk mutations impacts on the regulation of specific binding partner genes, including Lis1. These subtle molecular events may represent a pathogenic pathway related to schizophrenia.

Blackwood DH, Fordyce A, Walker MT, St Clair DM, Porteous DJ, Muir WJ. Schizophrenia and affective disorders--cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet. 2001 Aug;69(2):428-33. Epub 2001 Jul 6. Abstract

Brandon NJ, Handford EJ, Schurov I, Rain JC, Pelling M, Duran-Jimeniz B, Camargo LM, Oliver KR, Beher D, Shearman MS, Whiting PJ. Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders. Mol Cell Neurosci. 2004 Jan;25(1):42-55. Abstract

Callicott JH, Straub RE, Pezawas L, Egan MF, Mattay VS, Hariri AR, Verchinski BA, Meyer-Lindenberg A, Balkissoon R, Kolachana B, Goldberg TE, Weinberger DR. Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8627-32. Epub 2005 Jun 6. Abstract

Devon RS, Anderson S, Teague PW, Burgess P, Kipari TM, Semple CA, Millar JK, Muir WJ, Murray V, Pelosi AJ, Blackwood DH, Porteous DJ. Identification of polymorphisms within Disrupted in Schizophrenia 1 and Disrupted in Schizophrenia 2, and an investigation of their association with schizophrenia and bipolar affective disorder. Psychiatr Genet. 2001 Jun;11(2):71-8. Abstract

Ekelund J, Hovatta I, Parker A, Paunio T, Varilo T, Martin R, Suhonen J, Ellonen P, Chan G, Sinsheimer JS, Sobel E, Juvonen H, Arajarvi R, Partonen T, Suvisaari J, Lonnqvist J, Meyer J, Peltonen L. Chromosome 1 loci in Finnish schizophrenia families. Hum Mol Genet. 2001 Jul 15;10(15):1611-7. Abstract

Ekelund J, Hennah W, Hiekkalinna T, Parker A, Meyer J, Lonnqvist J, Peltonen L. Replication of 1q42 linkage in Finnish schizophrenia pedigrees. Mol Psychiatry. 2004 Nov;9(11):1037-41. Abstract

Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry. 2005 Jan;10(1):40-68; image 5. Review. Erratum in: Mol Psychiatry. 2005 Apr;10(4):420. Mol Psychiatry. 2005 Aug;10(8):804. Abstract

Hennah W, Varilo T, Kestila M, Paunio T, Arajarvi R, Haukka J, Parker A, Martin R, Levitzky S, Partonen T, Meyer J, Lonnqvist J, Peltonen L, Ekelund J. Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects. Hum Mol Genet. 2003 Dec 1;12(23):3151-9. Epub 2003 Oct 7. Abstract

Hodgkinson CA, Goldman D, Jaeger J, Persaud S, Kane JM, Lipsky RH, Malhotra AK. Disrupted in schizophrenia 1 (DISC1): association with schizophrenia, schizoaffective disorder, and bipolar disorder. Am J Hum Genet. 2004 Nov;75(5):862-72. Epub 2004 Sep 22. Abstract

Lewis DA, Glantz LA, Pierri JN, Sweet RA. Altered cortical glutamate neurotransmission in schizophrenia: evidence from morphological studies of pyramidal neurons. Ann N Y Acad Sci. 2003 Nov;1003:102-12. Review. Abstract

Lipska BK, Peters T, Hyde TM, Halim N, Horowitz C, Mitkus S, Shannon Weickert C, Matsumoto M, Sawa A, Straub R, Vakkalanka R, Herman MM, Weinberger DR, Kleinman JE. Differential expression in schizophrenia of a DISC1 molecular pathway and association with DISC1 SNPs. Soc Neurosci Abstract, SFN Annual Meeting, Washington DSC, 2005.

Millar JK, Christie S, Anderson S, Lawson D, Hsiao-Wei Loh D, Devon RS, Arveiler B, Muir WJ, Blackwood DH, Porteous DJ. Genomic structure and localisation within a linkage hotspot of Disrupted In Schizophrenia 1, a gene disrupted by a translocation segregating with schizophrenia. Mol Psychiatry. 2001 Mar;6(2):173-8. Abstract

Ozeki Y, Tomoda T, Kleiderlein J, Kamiya A, Bord L, Fujii K, Okawa M, Yamada N, Hatten ME, Snyder SH, Ross CA, Sawa A. Disrupted-in-Schizophrenia-1 (DISC-1): mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth. Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):289-94. Epub 2002 Dec 27. Erratum in: Proc Natl Acad Sci U S A. 2004 Sep 21;101(38):13969. Abstract

View all comments by Barbara K. LipskaComment by:  Akira Sawa, SRF Advisor
Submitted 12 January 2006
Posted 12 January 2006

I found the paper by Kholmanskikh and colleagues, which proposes a novel role for LIS1 in neuronal motility by bridging calcium signaling to Cdc42, of great interest for schizophrenia research. LIS1 was originally identified as the causative gene for lissencephaly, but cascades that include LIS1 may have implications for schizophrenia. Several groups, including ours, have reported that a candidate gene product for schizophrenia, DISC1, forms a protein complex with LIS1 (Brandon et al., 2004; Kamiya et al., 2005).

My collaborators, Brian Kirkpatrick and Rosy Roberts, have observed and presented data that DISC1 immunoreactivity is enriched in some (but not all) of the postsynaptic densities, where Rho-family GTPases, such as Cdc42, also occur and regulate synaptic functions (Society for Neuroscience Meeting, 2004). Many of us agree that schizophrenia is, at least in part, a disorder of synapses. Taken all together, it may be useful to have a working hypothesis that a candidate susceptibility gene product for schizophrenia, DISC1, may have an additional role in regulating synaptic functions via Rho-family GTPases, probably in some association with LIS1.

This paper may attract researchers on schizophrenia in another context. The authors used D-serine as a trigger of calcium signaling via activation of the NMDA receptor. Although several genes coding for proteins that are involved in synthesis and degradation of D-serine have been associated with schizophrenia, pathophysiological roles for D-serine remain to be elucidated. In this sense, the impact of D-serine in activation of Cdc42 and synaptic morphology may have implications for schizophrenia research. Personally speaking, it is the most interesting point in this paper that the authors use D-serine in this type of experiment.

View all comments by Akira Sawa

Comments on Related News

Related News: Messing with DISC1 Protein Disturbs Development, and More

Comment by:  Anil Malhotra, SRF Advisor
Submitted 21 November 2005
Posted 21 November 2005

The relationship between DISC1 and neuropsychiatric disorders, including schizophrenia, schizoaffective disorder, and bipolar disorder, has now been observed in several studies. Moreover, a number of studies have demonstrated that DISC1 appears to impact neurocognitive function. Nevertheless, the molecular mechanisms by which DISC1 could contribute to impaired CNS function are unclear, and these two papers shed light on this critical issue.

Millar et al. (2005) have followed the same strategy that they so successfully utilized in their initial DISC1 studies, identifying a translocation that associated with a psychotic illness. In contrast to DISC1, in which a pedigree was identified with a number of translocation carriers, this manuscript is based upon the identification of a single translocation carrier, who appears to manifest classic signs of schizophrenia, without evidence of mood dysregulation. Two genes are disrupted by this translocation: cadherin 8 and phosphodiesterase 4B (PDE4B). The researchers' elegant set of experiments provides compelling biological evidence that PDE4B interacts with DISC1 and suggests a mechanism mediated by cAMP for DISC1/PDE4B effects on basic molecular processes underlying learning, memory, and perhaps psychosis. It remains possible that PDE4B (and DISC1) are proteins fundamentally involved in cognitive processes, and that the observed relationship to psychotic illnesses represents a final common pathway of neurocognitive impairment. This would be consistent with data from our group (Lencz et al., in press) demonstrating that verbal memory impairment specifically predicts onset of psychosis in at-risk subjects. Similarly, Burdick et al. (2005) found that our DISC1 risk genotypes (Hodgkinson et al., 2004) were associated with impaired verbal working memory. Finally, Callicott et al. (2005) found that a DISC1 risk SNP, Ser704Cys, predicted hippocampal dysfunction, an SNP which we (DeRosse et al., unpublished data) have also found to link with the primary psychotic symptoms (persecutory delusions) manifested by the patient in the Millar et al. study. This body of evidence supports the notion that these proteins play fundamental roles in the key clinical manifestations of schizophrenia.

Kamiya et al. (2005) provide another potential mechanism for these effects, suggesting that a DISC1 mutation may disrupt cerebral cortical development, hinting that studies examining the role of DISC1 genotypes on brain structure and function in the at-risk schizophrenia pediatric patients may be fruitful.

Taken together, these papers add considerable new data suggesting that DISC1 plays a key role in the etiology of schizophrenia, and places DISC1 at the forefront of the rapidly growing body of schizophrenia candidate genes.

Burdick KE, Hodgkinson CA, Szeszko PR, Lencz T, Ekholm JM, Kane JM, Goldman D, Malhotra AK. DISC1 and neurocognitive function in schizophrenia. Neuroreport 2005; 16(12):1399-1402. Abstract

Callicott JH, Straub RE, Pezawas L, Egan MF, Mattay VS, Hariri AR, Verchinski BA, Meyer-Lindenberg A, Balkissoon R, Kolachana B, Goldberg TE, Weinberger DR. Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc Natl Acad Sci USA 2005; 102(24): 8627-8632. Abstract

Hodgkinson CA, Goldman D, Jaeger J, Persaud S, Kane JM, Lipsky RH, Malhotra AK. Disrupted in Schizophrenia (DISC1): Association with schizophrenia, schizoaffective disorder, and bipolar disorder. Am J Hum Genet 2004; 75:862-872. Abstract

Lencz T, Smith CW, McLaughlin D, Auther A, Nakayama E, Hovey L, Cornblatt BA. Generalized and specific neurocognitive deficits in prodromal schizophrenia. Biological Psychiatry (in press).

View all comments by Anil Malhotra

Related News: Messing with DISC1 Protein Disturbs Development, and More

Comment by:  Angus Nairn
Submitted 29 December 2005
Posted 31 December 2005
  I recommend the Primary Papers

This study describes an interesting genetic link between PDE4B (phosphodiesterase 4B) and schizophrenia that may be related to a physical interaction with DISC1 (disrupted in schizophrenia 1), another gene associated with the psychiatric disorder. The study is highly suggestive of a role for the PDE4B/DISC1 complex in schizophrenia. However, the mechanistic model suggested by the authors whereby DISC1 sequesters PDE4B in an inactive state seems overly speculative, given the results presented in this paper and in prior studies that have examined the regulation of PDE4B by phosphorylation in the absence of DISC1.

View all comments by Angus Nairn

Related News: Messing with DISC1 Protein Disturbs Development, and More

Comment by:  Patricia Estani
Submitted 2 January 2006
Posted 2 January 2006
  I recommend the Primary Papers

Related News: Messing with DISC1 Protein Disturbs Development, and More

Comment by:  Ali Mohammad Foroughmand
Submitted 16 December 2006
Posted 16 December 2006
  I recommend the Primary Papers