202213-30 - Mar Fatjó-Vilas

Targeting mRNAs condensates in neurites for a better understanding of synaptic plasticity dysfunction in schizophrenia

Each neuron is connected to another 1000 neurons, creating an incredibly complex network of communication. The synapse is the principal means of communication between neurons and, therefore, central to all brain functions. Not surprisingly, disturbances in synaptic function and connectivity have become highly relevant when trying to understand the origin of mental disorders. In particular, numerous genetic, neuroimaging and neuropathological evidence converge into the view of schizophrenia (SCZ) as a neurodevelopmental disorder associated with synaptic dysfunctions. Despite these important advances, the molecular mechanisms involved in synaptic dysfunctions are mostly unknown. To deepen into these mechanisms, we propose to focus on the “internal communication” of neurons: in mechanisms that regulate the transport and localisation of the mRNA from the cell body to the synapse. The mRNA is the resulting molecule of the transcription (or “the reading” of the genes in the cell nucleus), and the type, quantity and quality of mRNAs are essential for the final availability of the necessary proteins at the synapse. To travel through long distances in neurons, mRNAs must form condensates that can be conveniently distributed to synapses. Then, the assembly of mRNAs into RNA condensates is currently proposed as a crucial mechanism for the synapsis homeostasis.
Our preliminary analyses indicate that schizophrenia-associated genetic variants are enriched in genes that encode for mRNAs localised in these condensates. Therefore, we hypothesise that imbalances in mRNA condensates may play a role in the synaptic dysfunction in SCZ and that such imbalances are associated with the genetic individual genetic makeup.
Furthermore, as childhood and adolescent-onset forms of SCZ are associated with a higher genetic burden, we expect that imbalances in mRNA condensates will be more prominent in early-onset SCZ. To test these hypotheses, we propose to develop a project that integrates genomic, transcriptomic and neuroimaging into three main approaches.
First, we will study the mRNA condensates in experimentally obtained neurons (from blood samples of early- and adultonset SCZ patients and healthy controls). With this, we will answer whether there are differences in composition, quantity and sequence of these mRNAs between patients and controls.
Second, analysing the complete genome of early and adult-onset patients and healthy controls, we will investigate whether small differences in the genes related to the mRNA condensates contribute to the development of the disorder and its earlier onset.
Third, we will analyse whether the genes related to the mRNA condensates and their expression are related to brain connectivity differences through brain magnetic resonance images from patients and controls.
We strongly believe that our study will provide novel insights into the biological origin of SCZ and that, by generating connections between cellular, genetic and neurobiological data, we will foster the identification of markers with applicability in improving the detection, diagnosis and treatment of schizophrenia.

Fundació La Marató de TV3

148.156,25 €