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Millar JK, Pickard BS, Mackie S, James R, Christie S, Buchanan SR, Malloy MP, Chubb JE, Huston E, Baillie GS, Thomson PA, Hill EV, Brandon NJ, Rain JC, Camargo LM, Whiting PJ, Houslay MD, Blackwood DH, Muir WJ, Porteous DJ. DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science. 2005 Nov 18 ; 310(5751):1187-91. Pubmed Abstract

Comments on News and Primary Papers
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.

References:
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

Primary Papers: DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling.

Comment by:  Robert Peers
Submitted 6 December 2005
Posted 19 December 2005

PDE 4B enzyme activity is increased by PKA activation, hence, the suggested use of PDE inhibitors (like rolipram) in schizophrenia. I have another suggestion, especially because rolipram has unacceptable side-effects. Lauren Marangell's group in Texas (Mirnikjoo et al., 2001) has found that long-chain omega-3 essential fatty acids inhibit several protein kinases, including PKA.

Not only does this observation suggest one mechanism for the suggested benefits of omega-3 treatment of schizophrenia, but it also makes one wonder about the role of dietary omega-3 deficiency in causing or aggravating schizophrenia, especially during gestation, infancy, childhood, and adolescence, when unregulated PDE 4B activity could gravely affect neural development, contributing to schizophrenia pathogenesis.

Such deficiency may have begun, in industrial Western populations, when national fish consumption began to decline during the nineteenth century. Schizophrenia patients—and their mothers—in Western nations tend to eat a diet rich in saturated fats and low in omega-3, and have a worse outcome than in poorer nations, like India and Nigeria, where this dietary pattern is reversed. In 1977, Sartorius and colleagues concluded that the prognosis in schizophrenia, diagnosed by strict criteria, was considerably better in the collaborating centers in poorer nations, especially in India and Nigeria, than in the US, UK, or Denmark (Sartorius, 1977). An important re-analysis of the WHO study was made in 1988, by O and E Christensen in Denmark, who showed that 97 percent of the variance in outcome in the WHO study was explained by diet; in particular, low saturated fat intake combined with essential fatty acids from plant foods and seafood to explain the distinctly better outcome in Agra and Ibadan (Christensen and Christensen, 1988).

It is on this solid basis that some schizophrenia researchers (e.g., Scottish researcher Dr Iain Glen and his colleague Malcolm Peet in Sheffield), aware that dietary fatty acids influence brain membrane composition, are actively pursuing lipid nutrition as the most promising area of diet to improve schizophrenia outcome. Watch this space!

References:
Mirnikjoo B, Brown SE, Kim HF, Marangell LB, Sweatt JD, Weeber EJ. Protein kinase inhibition by omega-3 fatty acids. J Biol Chem. 2001 Apr 6;276(14):10888-96. Epub 2001 Jan 10. Abstract

Sartorius N, Jablensky A, Shapiro R. Two-year follow-up of the patients included in the WHO International Pilot Study of Schizophrenia. Psychol Med. 1977 Aug 1;7(3):529-41. Abstract

Christensen O, Christensen E. Fat consumption and schizophrenia. Acta Psychiatr Scand. 1988 Nov 1;78(5):587-91. Abstract

View all comments by Robert PeersComment 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 NairnComment by:  Patricia Estani
Submitted 2 January 2006
Posted 2 January 2006
  I recommend the Primary Papers

Primary Papers: DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling.

Comment by:  Miles Houslay
Submitted 7 January 2006
Posted 7 January 2006
  I recommend this paper

Response to comment by Angus Nairn
Thanks for your comment, Angus. With respect to the model proposed in our paper (Millar et al., 2005), perhaps it wasn't clear enough. However, the model proposed in this study envisages that DISC1 sequesters PDE4B in a "low(er) activity state," and most definitely not in an inactive state. Then it is suggested that activation of PKA by elevated cAMP levels allows, in these differentiated cells, for the release of PKA phosphorylated PDE4B in a "high(er) activity state." Interaction with DISC1 does not affect per se the activity of PDE4B in our hands. PDE4B does not need to be phosphorylated by PKA to be active (see, e.g., MacKenzie et al., 2002).

Note that PDE4 isoforms play a key role in underpinning compartmentalized cAMP signaling through interacting with distinct proteins in cells (Baillie et al., 2005; Baillie and Houslay, 2005; Houslay et al., 2005). It may well be that PDE4B released from DISC1 interacts with other protein(s) in these cells and thereby exerts functional effects. The precedent for this comes from studies on the PDE4D5 isoform, which on release from RACK1 interacts with β-arrestin and regulates β2-adrenoceptor functioning. I trust that this clarifies the situation.

References:
MacKenzie SJ, Baillie GS, McPhee I, MacKenzie C, Seamons R, McSorley T, Millen J, Beard MB, van Heeke G, Houslay MD. Long PDE4 cAMP specific phosphodiesterases are activated by protein kinase A-mediated phosphorylation of a single serine residue in Upstream Conserved Region 1 (UCR1). Br J Pharmacol. 2002 Jun;136(3):421-33. Abstract

Baillie GS, Houslay MD. Arrestin times for compartmentalised cAMP signalling and phosphodiesterase-4 enzymes. Curr Opin Cell Biol. 2005 Apr;17(2):129-34. Review. Abstract

Baillie GS, Scott JD, Houslay MD. Compartmentalisation of phosphodiesterases and protein kinase A: opposites attract. FEBS Lett. 2005 Jun 13;579(15):3264-70. Epub 2005 Apr 14. Review. Abstract

Houslay MD, Schafer P, Zhang KY. Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discov Today. 2005 Nov 15;10(22):1503-19. Review. Abstract

View all comments by Miles HouslayComment by:  Ali Mohammad Foroughmand
Submitted 16 December 2006
Posted 16 December 2006
  I recommend the Primary Papers