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Messing with DISC1 Protein Disturbs Development, and More

20 November 2005. When it rains, it pours, they say, and that may be the case with two major papers, appearing in rapid succession and unleashing a torrent of new information about the role of the DISC1 gene in mental illness. DISC1 (disrupted in schizophrenia 1) has been identified in several families with schizophrenia and other major mental disorders, but just how mutations in this gene precipitate illness is unclear. A new report from Kirsty Millar, David Porteous, and colleagues in Science reveals that DISC1 partners with phosphodiesterase 4B, an enzyme that regulates levels of cAMP in neurons. This link between DISC1 and the cAMP signaling pathway, which functions in cognition, memory, and mood, could help explain how the altered genes can elicit psychiatric symptoms via faulty neurotransmitter signaling.

The pathogenesis of schizophrenia has a developmental component as well, and in another paper, Akira Sawa and colleagues from the US and Japan explore the impact of the DISC1 translocation on brain development. Writing in Nature Cell Biology, the group reports that a carboxy-terminal truncated form of DISC1 disrupts neuronal migration and axon growth by destabilizing the dynein motor and disrupting microtubule dynamics. Their work explains how the translocation involving DISC1 could contribute to the changes in neural architecture that have been reported in the brains of people with schizophrenia.

It was a rearranged chromosome in a large Scottish family with frequent mental illness that led Porteous and colleagues to DISC1 several years ago (Millar et al., 2000). In their new paper, Millar and collaborators in Edinburgh, Glasgow, France, and the UK report the discovery of a different rearrangement in another person with schizophrenia that disrupts two genes, phosphodiesterase 4B (PDE4B) and cadherin 8. Of the two, they chose to focus on PDE4B, an enzyme which degrades and inactivates the second messenger cAMP. They showed that expression of PDE4B was decreased in the patient with the translocation. Add to that a previous observation (Brandon et al., 2004) that DISC1 and PDE4B interact in a two-hybrid screen, and the researchers were off and running, looking for a link between the two proteins in cells.

Several approaches established that DISC1 and PDE4B were directly physically associated in neurons. Standard coexpression and coimmunoprecipitation experiments revealed that multiple isoforms of PDE4B directly interacted with the N-terminal end of DISC1. The endogenous PDE4B1 isoform coprecipitated with a 71 kDa form of DISC1. Cell fractionation showed that both of the proteins were most abundant in the mitochondria-enriched fraction, and fluorescence microscopy revealed an overlapping distribution in that compartment.

PDE4B enzyme activity is increased by elevation of cAMP and activation of PKA, which phosphorylates a regulatory domain on PDE4B. Using pharmacological elevators of cAMP, Millar and coworkers showed that increasing cAMP caused a decrease in the association of PDE4B with DISC1, and this effect required PKA activity. Their results support the idea that DISC1 binds a dephosphorylated, inactive form of PDE4B. When cAMP levels go up, PDE4B becomes phosphorylated and active, and the proteins dissociate. Having shown that chromosomal translocations involving PDE4B or DISC1 decreased expression of their respective proteins by about half, and that the interaction between the two proteins is dynamic, the authors conclude by speculating that “functional variation in DISC1 and/or PDE4 will modulate their interaction and affect mitochondrial cAMP catabolism with a concomitant physiological and psychiatric outcome.”

In a perspective piece in the same issue of Science, Sawa and Solomon Snyder from Johns Hopkins ask whether PDE4B presents a new therapeutic target for schizophrenia. If DISC1 deficiency results in higher PDE4 activity, it would make sense to look for agents that increase binding of DISC1 to PDE4B, or even direct inhibitors of the enzyme, like the antidepressant rolipram (see SRF related news story). But, they point out, it’s hard to predict the effects of elevating cAMP, which serves different functions in different areas of the brain. Nonetheless, they conclude that the work provides a unifying link between schizophrenia and mood disorders, which often occur in the same families, and sometimes in the same individuals, as in schizoaffective disorder.

In his paper in Nature Cell Biology, Sawa has another story to tell about DISC1 and its role in neurodevelopment. In this study, first author Atsushi Kamiya and coworkers show that DISC1 is part of the dynein motor complex, along with the developmentally important proteins NUDEL and LIS1, and stabilizes the complex at the centrosome, contributing to normal microtubule dynamics. The carboxy-terminal truncation of DISC1 that occurs in the Scottish family acts like a dominant negative, knocking normal DISC1 out of the dynein complex and impairing motor activity.

In neurons, the dynein motor and its effects on microtubule organization help drive neuronal migration and axon formation during development. When the researchers used RNAi to lower DISC1 expression in neurons in culture, or expressed the truncated DISC1, they observed decreased neurite outgrowth. Moving in vivo, they performed in utero electroporation to deliver RNAi or mutated DISC1 to fetal rat cortical neurons, and showed decreased migration of neurons during cortical development. Neurons that did make it to their correct positions had impaired orientation, polarity, and dendritic arborization. While nearly complete knockdown of DISC1 with a potent RNAi caused almost full inhibition of migration, the mutant DISC1 produced a partial migration defect, consistent with the subtle developmental changes seen in brains of schizophrenic patients.

Whether the DISC1 gene translocation in people results in a deficiency of protein, or the production of a mutant protein, or both, is still an open question, but either could account for what Sawa and colleagues propose to be a key developmental impairment resulting from a loss of DISC1 function. Importantly, both the PDE4 and dynein connections for DISC1 allow for dose-dependent partial effects that could produce a spectrum of disorders, with various combinations of schizophrenic and affective symptoms, stemming from both developmental and functional roots.—Pat McCaffrey.

References:
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;310:1187-1191. Abstract

Sawa A, Snyder SH. GENETICS: Two Genes Link Two Distinct Psychoses. Science. 2005 Nov 18;310:1128-1129. 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. Nature Cell Biology. 2005 November 20. Advance online publication. 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...  Read more


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...  Read more


View all comments by Robert Peers

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


Comment 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;   Read more


View all comments by Miles Houslay

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