Schizophrenia Research Forum - A Catalyst for Creative Thinking
Home Profile Membership/Get Newsletter Log In Contact Us
 For Patients & Families
What's New
Recent Updates
SRF Papers
Current Papers
Search All Papers
Search Comments
Research News
Conference News
Plain English
Current Hypotheses
Idea Lab
Online Discussions
Virtual Conferences
What We Know
Animal Models
Drugs in Trials
Research Tools
Community Calendar
General Information
Member Directory
Researcher Profiles
Institutes and Labs
About the Site
SRF Team
Advisory Board
Support Us
How to Cite
Fan (E)Mail
The Schizophrenia Research Forum web site is sponsored by the Brain and Behavior Research Foundation and was created with funding from the U.S. National Institute of Mental Health.
Research News
back to News Search
DISC1 2010—DISC1 Interactors Reviewed

As part of our ongoing coverage of DISC1 2010, held 3-6 September 2010, in Edinburgh, the United Kingdom, we bring you a meeting missive from Elise Malavasi, a graduate student at the University of Edinburgh.

13 September 2010. Co-organizer Douglas Blackwood of the University of Edinburgh kicked off the first full day of the meeting—Saturday, 4 September—with two sessions on "Genotype and Phenotype." David St Clair from the University of Aberdeen, U.K., opened the first session of the day by summarizing the existing genetic evidence supporting a role for the DISC1 interactome in schizophrenia. PDE4B, PCM1, Ndel1, and Nde1 opened the list of suspects, as both genetic and biological evidence for a link with schizophrenia converge on these genes. Although the evidence for genetic association of APP with schizophrenia is still limited, this newcomer in the family of DISC1 binding partners was mentioned by virtue of its recently reported role as upstream regulator of DISC1 function in neuronal migration (Young-Pearse et al., 2010). Moving on to the GSK3β/β-catenin pathway, St Clair pointed out that although no schizophrenia-associated mutations in GSK3β or β-catenin have yet been detected, their downstream effector TCF4 (see SRF related news story), is a well-replicated genetic risk factor, strengthening the evidence for the involvement of this pathway in schizophrenia. St Clair concluded by remarking that two of the pathways modulated by DISC1—AKT-mTOR and Kal7-Rac1—converge on the translation initiation factor eIF4E, which has already been implicated in autism and fragile X mental retardation, indicating that different forms of mental illness may share a similar developmental origin.

In the following talk, Hugh Gurling from University College London, U.K., focused on one member of the DISC1 interactome, PCM1, as a genetic risk factor for schizophrenia. Gurling summarized the wealth of evidence from family-based and genomewide linkage studies, as well as association studies, implicating PCM1 in schizophrenia. Upon testing for epistasis between PCM1 and DISC1, Gurling and colleagues found some evidence of interaction, although it wasn’t clear whether it was synergistic or repulsive. Resequencing of PCM1 in schizophrenics who had inherited risk-conferring PCM1 haplotypes led Gurling and colleagues to the discovery of three potentially etiogenic mutations: an amino acid substitution in exon 24 that is likely to induce conformational changes in the protein and alter its phosphorylation status; a mutation in exon 2 that changes a transcription factor binding site; and a base pair change that alters a splice site. Future studies will be aimed at discovering more variants in the PCM1 gene and determining which ones are pathological. Gurling provided further evidence that genetic variation in the PCM1 gene is likely to affect brain function, as illustrated by a brain imaging study showing that the magnitude of textural abnormalities in the grey matter of schizophrenia patients is influenced by schizophrenia-associated alleles of PCM1 (for more details, see SRF related news story). Additional evidence implicating PCM1 in the etiopathogenesis of schizophrenia comes from an unpublished study comparing changes in gene expression in the mouse brain after treatment with the antipsychotic clozapine or the antidepressant haloperidol. In this study, PCM1 was selectively downregulated by clozapine. Gurling’s conclusion was that variants of PCM1 that affect either its positioning at the centrosome or its interaction with key binding partners could be involved in the pathogenesis of a subtype of schizophrenia.

PCM1 remained at the center of attention in the last talk of the session, delivered by Sharon Eastwood from the University of Oxford, U.K. In line with evidence supporting a role for DISC1 in the recruitment of PCM1 to the centrosome (see SRF related news story), Eastwood observed an effect of schizophrenia-associated DISC1 variants S704C and L607F on the centrosomal immunoreactivity of PCM1, both in transfected cell lines and in human brains. In addition, she found an effect of L607F on neurotransmitter release from transfected cell lines. When looking at human brain sections, Eastwood found that the centrosomal localization of PCM1 is restricted to glial cells, and she pointed out that although DISC1 expression in glial cells has been reported by independent studies, our understanding of the function of DISC1 in this subset of brain cells is still extremely limited. Variation at positions 607 and 704 of DISC1 influenced PCM1 positioning at the centrosome in glial cells in Eastwood's studies, with potential cumulative effects, but no differences in the centrosomal abundance of PCM1 were observed between schizophrenics and controls. Eastwood confirmed the additive effect of the two DISC1 SNPs on PCM1 centrosomal abundance in overexpression studies in a rat glioma cell line, and plans to extend her functional studies on these variants by testing their potential effect on the centrosomal localization of other DISC1 binding partners. Other experiments will be aimed at exploring the role of DISC1 in glial cell physiology.—Elise Malavasi.

Submit a Comment on this News Article
Make a comment on this news article. 

If you already are a member, please login.
Not sure if you are a member? Search our member database.

*First Name  
*Last Name  
Country or Territory  
*Login Email Address  
*Confirm Email Address  
*Confirm Password  
Remember my Login and Password?  
Get SRF newsletter with recent commentary?  
Enter the code as it is shown below:
This code helps prevent automated registrations.

Please note: A member needs to be both registered and logged in to submit a comment.


(If coauthors exist for this comment, please enter their names and email addresses at the end of the comment.)


SRF News
SRF Comments
Text Size
Reset Text Size
Copyright © 2005- 2016 Schizophrenia Research Forum Privacy Policy Disclaimer Disclosure Copyright