We identify key differences in the expression and subcellular distribution of SynGAP isoforms!!
SynGAP Splice Variants Display Heterogeneous Spatio-Temporal Expression And Subcellular Distribution In The Developing Mammalian Brain
We found distinctive developmental expression patterns for SynGAP isoforms in five mouse brain areas. Particularly noticeable was the delayed expression of SynGAP-α1 isoforms, which directly bind to PSD-95, in cortex and hippocampus during the first two weeks of postnatal development. Suggesting that during this period other isoforms would have a more prominent role. Furthermore, we observed subcellular localization differences between isoforms, particularly throughout postnatal development. Consistent with previous reports, SynGAP was enriched in the postsynaptic density in the mature forebrain. However, SynGAP was predominantly found in non-synaptic locations in a period of early postnatal development highly sensitive to SynGAP levels. While, α1 isoforms were always found enriched in the postsynaptic density, α2 isoforms changed from a non-synaptic to a mostly postsynaptic density localization with age and β isoforms were always found enriched in non-synaptic locations. The differential expression and subcellular distribution of SynGAP isoforms may contribute to isoform-specific regulation of small GTPases, explaining SynGAP pleiotropy.
Published the SynGO Collaborative Project, Dedicated to the Systematic Annotation of Synaptic Proteins.
SynGO: An Evidence-Based, Expert-Curated Knowledge Base for the Synapse
Synapses are fundamental information-processing units of the brain, and synaptic dysregulation is central to many brain disorders (“synaptopathies”). However, systematic annotation of synaptic genes and ontology of synaptic processes are currently lacking. We established SynGO, an interactive knowledge base that accumulates available research about synapse biology using Gene Ontology (GO) annotations to novel ontology terms: 87 synaptic locations and 179 synaptic processes. SynGO annotations are exclusively based on published, expert-curated evidence. Using 2,922 annotations for 1,112 genes, we show that synaptic genes are exceptionally well conserved and less tolerant to mutations than other genes. Many SynGO terms are significantly overrepresented among gene variations associated with intelligence, educational attainment, ADHD, autism, and bipolar disorder and among de novo variants associated with neurodevelopmental disorders, including schizophrenia. SynGO is a public, universal reference for synapse research and an online analysis platform for interpretation of large-scale -omics data ( https://syngoportal.org and http://geneontology.org).
Metazoan Evolution of Glutamate Receptors Reveals Unreported Phylogenetic Groups and Divergent Lineage-Specific Events
Abstract: Glutamate receptors are divided in two unrelated families: ionotropic (iGluR), driving synaptic transmission, and metabotropic (mGluR), which modulate synaptic strength. The present classification of GluRs is based on vertebrate proteins and has remained unchanged for over two decades. Here we report an exhaustive phylogenetic study of GluRs in metazoans. Importantly, we demonstrate that GluRs have followed different evolutionary histories in separated animal lineages. Our analysis reveals that the present organization of iGluRs into six classes does not capture the full complexity of their evolution. Instead, we propose an organization into four subfamilies and ten classes, four of which have never been previously described. Furthermore, we report a sister class to mGluR classes I-III, class IV. We show that many unreported proteins are expressed in the nervous system, and that new Epsilon receptors form functional ligand-gated ion channels. We propose an updated classification of glutamate receptors that includes our findings.
Our work on the evolution of Toll-like receptors in metazoans has been published in Frontiers in Immunology
Our work on the chronic effects of MAPK pathway inhibition in the context of SYNGAP1 deficiency has been published in Pharmacological Reports.
In just a few days our pop-science book entitled ‘La Neurogenómica. La genética del cerebro’ will be for sale all over Spain and Mexico.
The book, which is published by National Geographic, addresses the most recent findings about how genes govern brain function.
This book is part of the larger collection ‘Los Desafios de la Ciencia‘.
The Spanish Ministry for Economy and Competitivity will keep funding our research network ‘Synaptic Role in Cognitive Disabilities Network‘ (http://www.syncogdis.org/).
In this network we have brought together scientists from many different disciplines with the goal to accelerate research in the study of the synaptic role in brain disorders such as neurodevelopmental conditions and neurodegenerative diseases.
An European scientific consortium lead by our research group has been granted with an ERA-NET NEURON grant to support the research project “Synaptic Dysfunction in Intellectual Disability Caused by SYNGAP1. Translational Research to Develop Human Models and Advance Pharmacological Treatments”. The main goal of this project is to make iPSCs harbouring SYNGAP1 mutations causing intellectual disability and to use them to identify new potential treatments.
This project will start in the first semester of 2018 and finish in 2021.
We have published a meta-analysis paper where we critically review the proteomics data acquired over the year to elucidate synaptic mechanism of Mental Disease. We suggest that future research in the field will require higher levels of standardization and larger-scale experiments to address the challenge posed by biological and methodological variability.
Rita Reig-Viader, Carlos Sindreu and Àlex Bayés.
Synaptic proteomics as a means to identify the molecular basis of mental illness: are we getting there?
Progress in Neuropsychopharmacology and Biological Psychiatry. 2017 Sep 20. pii: S0278-5846(17)30461-X.