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The synaptic proteome of the zebrafish opens the door to understanding neurological and psychiatric disorders

A group of scientists of the Sant Pau Biomedical Research Institute (IIB Sant Pau), the Autonomous University of Barcelona and the University of Edinburgh have successfully characterized the synaptic proteome of the zebrafish. The study, published in Nature Communications, has also revealed the proteome of the synaptic structure known as post-synaptic density (PSD). This research has enabled a deeper knowledge of how evolution has promoted greater complexity in the synaptic proteome, facilitating greater diversity in the intellectual capacities of vertebrates.

“The most important differences have been observed when comparing the PSD of the fish to that of a mouse," as Dr. Àlex Bayés, Head of the Molecular Physiology of the Synapse Laboratory at IIB Sant Pau, and lead author of the article, tells Biocores. “The synaptic proteome of the zebrafish is essentially similar to that of the mouse," says the scientist, although there are certain modifications. To the contrary, the comparison of the mouse and human proteomes reveals greater similarity, as they identified in research previously published in the journal PLOS One. The results obtained up to now have been published in a database freely accessible to any interested scientists.

Source: Marrabbio2 (Wikimedia)

A key tool to understanding neurological disorders

The identification of the synaptic proteome, or the set of proteins that play a fundamental role in neuronal synapses, has aroused growing interest in recent times. “They will lead not only to a more detailed characterization of the synaptic proteome but also of the impact of alterations in the proteinaceous inventory in the case of diseases, ontogenetic development and evolution”, states a member of the Goethe University research team in a review previously published in the journal Cell and Tissue Research.

In the past, synapses were considered mere connections between neurons. Now, however, they are recognized as highly sophisticated computational units built from proteomes with more than a thousand proteins. Dysfunctions or alterations in synaptic proteomes lead to the development of over 130 synaptopathies, psychiatric and neurological disorders, including autism, schizophrenia or mental disability. “Understanding the components that make up synaptic mechanisms is indispensable for their study, as well as for modeling human diseases that present synaptic dysfunction," says Bayés.

His team decided to characterize the synaptic proteome of the zebrafish, as "its genomeImage provided by Àlex Bayés (IIB Sant Pau) is very well annotated, which has allowed us to carry out proteomic experiments with more accuracy," adds the scientist. Danio rerio is also a key model for the study of pathologies related with the brain. Therefore, it is being used increasingly in pharmacological research. First, the team of scientists carried out a structural analysis on the central synapses of the zebrafish to determine whether they presented PSD, and to know if they were characteristics also conserved in mammals. After examining Danio rerio's four main cerebral regions using transmission electron microscopy, researchers characterized its synaptic proteome using high-throughput mass spectrometry.

Electron microscopy image showing zebrafish synapses
Image provided by Àlex Bayés (IIB Sant Pau)

The article published in Nature Communications reveals that the zebrafish proteome had a lower number and fewer types of proteins in the PSD. “We have also seen that the diversity of proteins involved in the endocytosis of the neurotransmitter receptors is lower in the fish. These proteins are very important for the control of synaptic function and especially synaptic plasticity," states Àlex Bayés. His group has successfully found 3,640 synaptic proteins in this animal model, of which 1,758 are in the post-synaptic density. “The number of zebrafish PSD families was significantly lower than expected for zebrafish PSD proteins or mouse orthologues of zebrafish PSD proteins”, write the authors in their article.

The identification of the synaptic proteome in mice and human beings has allowed scientists to gain a better understanding of disorders such as schizophrenia or the fragile X syndrome . In the past, the characterization of the set of proteins that intervene in the synapse has also helped understand post-natal cerebral development in rodents and discover the role the synaptic proteome plays in cognitive capacities such as memory and learning or problems such as bipolar disorder. After determining the synaptic proteome in zebrafish and knowing the proteins involved in post-synaptic density, Bayés's team now hopes to discover the synaptic mechanisms involved in the pathophysiology of monogenic diseases that cause mental disability and autism. His group is working to apply biochemical and proteomic tools to understand the role played by genes such as SYNGAP1 and SHANK2, involved in neuronal communication and related with this type of disorders.