Decoding the contribution of genetically driven alternative polyadenylation to functional connectivity deficits in schizophrenia

• Applicant: Professor Dr. Michael J. Ziller
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Biological Psychiatry ; Cell Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 522705234

Schizophrenia (SCZ) is a highly polygenic disease with hundreds of associated common genetic variants. While individual genes located within specific risk loci have been characterized in great detail, it has become clear that any common molecular mechanism contributing to disease etiology must depend on their combined effects. However, such a polygenically driven mechanism remains elusive. We recently concluded the largest functional genomic study in the field of mental health. By combining induced pluripotent stem cells (iPSC), post mortem brain analysis and cell biology we identified the first polygenically driven molecular mechanism in neuronal cells from SCZ patients. This mechanism is characterized by the alternative polyadenylation of the 3’UTR (3’UTR-APA) of many transcripts related to synapse biology and neuronal activity and coincides with altered mRNA localization and changes in neuronal network micro-connectivity. In line with this finding, previous studies highlighted the role of the 3’UTR in mRNA stability and subcellular localization through inclusion of RNA regulatory elements such as binding sites for RNA binding proteins (RBPs) and motor protein, particularly in neurons. Thus, we aim here to go beyond these observations and dissect this new disease mechanism on a functional level. To that end, we will combine personalized in vitro models for SCZ with basic neuronal RNA biology to test the hypothesis that: polygenically driven de-regulation of RNA binding proteins (RBPs) in individuals with SCZ causes 3’UTR APA and impaired mRNA transport towards the synapse, contributing to synaptic deficits in SCZ. In particular, we will (i) pinpoint those genetically de-regulated RBPs that act in trans to cause 3’UTR-APA of synaptic and neuronal activity related transcripts in individuals with SCZ. (ii) Moreover, previous findings suggest that 3’UTR-APA leads to re-configuration of RBP binding sites, resulting in a loss of RNA regulatory elements critical for the binding of RNA transport proteins. Therefore, we will identify those mRNAs that are localized to the neurites of iPSC derived neurons, are subject to mis-localization, and 3’UTR-APA in individuals with SCZ. (iii) Lastly, our previous findings highlighted the autism risk gene SHANK3 as a key example subject to 3’UTR-APA in SCZ. The latter coincided with mis-localization of the respective transcript and protein, reduction in SHANK3 positive synapses and altered micro-connectivity of neuronal networks. In order to test the functional and physiological relevance of these molecular changes, we will establish a causal link between 3’UTR-APA of SHANK3 mRNA, its altered subcellular localization and changes in functional neuronal connectivity. Jointly, this research program will pinpoint the precise causes of 3’UTR-APA and establish genetically induced alteration of subcellular RNA localization as a new mechanism contributing to the molecular basis of SCZ.

• DFG Programme: Research Grants