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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 Paper and Primary News
Primary 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...  Read more

View all comments by Anil Malhotra

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...  Read more

View all comments by Robert Peers

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

Comment by:  Angus Nairn
Submitted 29 December 2005 Posted 31 December 2005
  I recommend this paper

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

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

Comment by:  Patricia Estani
Submitted 2 January 2006 Posted 2 January 2006
  I recommend this paper

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;   Read more

View all comments by Miles Houslay

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

Comment by:  Ali Mohammad Foroughmand
Submitted 16 December 2006 Posted 16 December 2006
  I recommend this paper
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