DISC1 and the Developmental Hypothesis of Schizophrenia
Tuesday, May 27, 2008
Presented By
Presented by Biochemical Pharmacology Discussion Group and the American Chemical Society's New York Section
Organizers: Julia Heinrich, PhD, Formerly with Wyeth Discovery Neuroscience and Robin Kleiman, PhD, Pfizer, Inc
Schizophrenia (SZ) is a psychiatric disorder characterized by thought disorder and cognitive deficits. Currently available antipsychotics provide relief of positive symptoms, but have limited therapeutic efficacy on negative and cognitive symptoms that typically preclude successful reintegration into society for many patients. The developmental hypothesis of SZ was originally based on observations that certain environmental factors and behavioral traits might lead to a predisposition for SZ. More recently it was broadened to include the influence of SZ susceptibility genes, of which Disrupted in Schizophrenia 1 (DISC1) is one of the most promising candidates. The DISC1 protein functions as a scaffold for multiple proteins, including nuclear distribution element-like 1 and phosphodiesterase 4B, which themselves are candidate SZ susceptibility genes. This symposium invites experts in the field of DISC1 biology to present their ideas on the etiology of SZ and how an understanding of DISC1 regulated pathways might relate to the development of new antipsychotic therapies.
1:00 pm
Introduction
1:15 pm
Centrosomal Pathway of DISC1 in Schizophrenia
Akira Sawa, MD, PhD, Johns Hopkins University School of Medicine Baltimore, Maryland
2:00 pm
Unraveling the Function of DISC1 through Components of the DISC1 Interactome and DISC1 Expression in the Brain
Nicholas Brandon, PhD, Wyeth Research, Princeton, New Jersey
2:45 pm
Coffee Break
3:15 pm
DISC1 and its Binding Partners: Impact on Schizophrenia-Related Clinical Traits
Katherine E. Burdick, PhD, North Shore Long Island Jewish Health System, Glen Oaks, New York
4:00 pm
A Mouse Mutagenesis Approach to Elucidating the Role of DISC1 in the Brain
Steven J. Clapcote, PhD, The University of Edinburgh, Scotland
4:45 pm
Closing Remarks
Akira Sawa, MD, PhD, Johns Hopkins University School of Medicine
I will provide new evidence that support a role for DISC1 in the centrosome, which is crucial for microtubule dynamics in cells and for proper formation of neuronal circuitry in developing brains. DISC1 forms a protein complex with PCM1 and Bardet-Biedl syndrome proteins through discrete binding domains at the centrosome. DISC1 and BBS4 act synergistically to recruit PCM1 and associated proteins to the centrosome. Disruption of the PCM1-DISC1-BBS4 pathway leads to profound defects in neuronal migration during cortical development. Finally, we report a pedigree in which a nonsense mutation in the PCM1 gene segregates with SZ-spectrum psychosis.
Unraveling the Function of DISC1 through Components of the DISC1 Interactome and DISC1 Expression in the Brain
Nicholas Brandon, Wyeth Research
An understanding of the biological role and significance of DISC1 in neuronal development and cell signaling has been greatly enhanced by the identification of DISC1 binding partners and an appreciation of its expression during development. I will give examples of both approaches as we continue to explore DISC1 biology and its relevance to disease etiology. I will present new data on the identity and function of synaptic forms of DISC1 in the hippocampus and describe new data on the key DISC1 interactor Ndel1, where we will show that the DISC1-regulated oligopeptidase activity of Ndel1 is critical for neurite outgrowth.
DISC1 and its Binding Pa