Networks of interacting proteins relevant in mood disorders and schizophrenia

Coordinator:    Prof. Dr. Erich Wanker
Institution: Max-Delbrück-Centrum für Molekulare Medizin (MDC) Berlin-Buch
The main objective of this subproject was the generation of an extensive network of interacting proteins playing a role in bipolar disorder (BPD) and schizophrenia (SCZ) using high throughput yeast two-hybrid (Y2H) and bioinformatic methods.
Using a rating system developed at the MDC, the quality of each PPI was assessed. This allowed to classify 128 PPIs as high confidence (HC), 108 (84%) of which were validated using a modified LUMIER method.
Genome-wide studies (GWAS) have shown that the protein ZNF804A is an important risk factor for BPDs and SCZs (O'Donovan et al., Nature Genetics, 2008). However, its function and effects remain unclear. Therefore, we have generated a network focused on this protein including 87 PPIs, of which 55 could be validated using the LUMIER assay.
Utilizing bioinformatic analyses, a zinc finger domain was identified in ZNF804A. Additionally, two further human proteins have been found (ZNF804B and GPATCH8) which show significant homology to ZNF804A and also have an N-terminal zinc finger domain.
Based on Gene Ontology analyses we could show that several interaction partners of ZNF804A are directly or indirectly involved in RNA splicing. Using a newly developed cell-based fluorescent gene reporter assay (Younis et al, Mol Cell Biol, 2010; Stoilov et al, PNAS, 2008) we could demonstrate that ZNF804A also has a function in this process: The increased production of ZNF804A FLAG-tagged proteins in HeLa cells significantly reduces RNA splicing.
GWAS were previously regarded as the only reliable method to identify new risk genes for BPDs and SCZs. We used a newly developed approach to filter our proteomic data set with the VEGAS method to identify 25 more of such genes. Interestingly they showed a significantly increased expression in the occipital lobe where only gray matter has so far been detected in SCZ patients. This led to the assumption that the visual cortex is responsible for all visual SSR failures due to neuroanatomical abnormalities. Evidence at the cellular level have yet to be provided. Based on our findings on the enrichment of splicing relevant proteins in SCZ relevant brain regions, we assume a significant metabolic RNA interference in the affected neurons. This theory is corroborated by several gene profiling studies, which show extensive differences in gene expression of SCZ patients (Silver et al, IJNP, 2011; Bullock et al, Am J Psychiatry, 2008.).


High confidence Y2H interaction network for major mood disorders and schizophrenia.

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