15 May, 2020

Characterization Molecular Axis – Schizophrenia (Basic Research)

CREATIO EXPANDS RESEARCH INITIATIVES TO SCHIZOPHRENIA AND CONTRIBUTES TO THE CHARACTERIZATION OF A NEW MOLECULAR AXIS RELEVANT FOR THE PATHOPHYSIOLOGY OF THE DISEASE

In this new publication, Creatio’s research team and the group led by Dr. Albert Giralt joined forces to discover the interplay between two molecular factors, Helios and WDFY1, that could help elucidating the link between immunity and schizophrenia.

Schizophrenia is a chronic debilitating neuropsychiatric disorder affecting approximately 1% of the population worldwide. Signs and symptoms may vary, but usually involve delusions, hallucinations with disorganized speech, thinking and behavior. Over the years, it has been proposed that one of the factors contributing to schizophrenia could be aberrant interaction of the immune system with the central nervous system although the molecular mechanisms have remained poorly understood.

Previous research directed by Creatio’s director, Dr. Canals, and by Dr. Giralt and had shown that Helios, a transcription factor classically reported as a potent regulator of molecular pathways related to immunity, was also involved in the neurodevelopment of striatum and hippocampus. Both brain regions are affected in schizophrenia patients. A high throughput RNAseq approach allowed the identification of Wdfy1 (WD Repeat and FYVE Domain Containing 1) gene as a core Helios target. The WDFY1 protein is an adaptor protein for the Toll-like receptor 3 and 4 (TLR3/4) signaling pathway and as such mediates the innate and adaptative immune responses. The present study shows that aberrantly and sustained upregulated levels of the Wdfy1 gene are a very specific and long-lasting molecular hallmark in mice devoid of Helios (He^−/− mice). Moreover, He^−/− mice display several schizophrenia-like phenotypes related to dysfunctions in the striatum and hippocampus. To validate the relevance of these observations with the disease, expression levels of WDFY1 protein were analyzed in patients and shown to be increased in the hippocampus and dorsolateral prefrontal cortex of schizophrenic patients, but not in the hippocampus of Alzheimer’s disease patients with an associated psychotic disorder underlining the specificity of the relationship between the marker and the disease. Deeper characterization was done in the mouse model and an increase in spine density was observed in medium spiny neurons (MSNs) with a decrease in the number and size of PSD-95-positive clusters in the stratum radiatum of the CA1. Interestingly, these phenotypes have been described in schizophrenic patients in previous studies. In addition, the observed alterations in structural synaptic plasticity are associated with level changes of neuronal NF-κB in the pyramidal layer of the CA1 in He^−/− mice, strengthening the link with the modulation of immune response. Taken altogether, the results demonstrate that the He^−/− mice are a valid model to study how alterations during the development of the central nervous system could account for molecular pathways typically involved with immunomodulatory processes that would later precipitate the appearance of neuropsychiatric disorders such as schizophrenic pathology.

Further research will be undertaken to describe in more detail the molecular mechanisms at work in schizophrenia and build models for drug discovery that could be exploited through the Avantdrug® platform Creatio just launched.

Creatio will proudly continue the fruitful collaboration set with the group of Dr. Giralt to characterize Ikaros family members such as Helios and to move forward to a possible cure for schizophrenia, a disease which still unfortunately requires lifelong treatment.