Discovered SETD5 role in preserving brain development and neuronal wiring
Neurodevelopmental disorders are a class of neurological and psychiatric disorders that occur during the developmental age. They include intellectual disabilities and autism spectrum disorders, which represent a variety of complex conditions caused by both genetic and environmental factors. A group of researchers from IRCCS Ospedale San Raffaele and from the Neuroscience Institute of the National Research Council – coordinated by Alessandro Sessa and Vania Broccoli – in collaboration with the University of Trento and Pisa, discovered the role a gene (called SETD5) whose mutation is linked to some forms of intellectual disabilities. The results, recently published in the prestigious journal Neuron, show that SETD5 encodes for a protein with a fundamental and unexpected role within the nucleus of neurons: ensuring the correct transcription of DNA information, a fundamental step in the process of proteins synthesis. The discovery paves the way for the identifications of new therapeutic targets.
Intellectual disabilities, as many other neurodevelopmental disorders, are highly complex conditions, that are associated with mutations in hundreds of different genes. Among them, there is SETD5. When it is no longer functioning, disabilities affecting both language and movement emerge, as well as behaviors typical of the obsessive-compulsive and autistic spectrum disorders. Although this was already known, to date it was not clear the exact function of SETD5, nor the mechanisms by which loss-of-function mutations of the gene affects primarily the development of the nervous system.
By studying both in vitro and animal models of the mutation, San Raffaele researchers discovered that SETD5 plays a key role in maintaining DNA structure and in allowing the transcription machinery to proper release the genetic information: to be used, this information must first be transcribed into another form – the RNA, a sort of carbon copy of the DNA – and taken out of the nucleus; SETD5 is involved in regulating this delicate process, which is particularly complex in nervous cells because of the long genes involved in their functioning.
«SETD5 represents a sort of "molecular architect" that regulates the complex organization of the DNA within neurons. Without it, the transcription process is altered» explains Alessandro Sessa, coordinator and first author of the study. «As a consequence, mice lacking the Setd5 gene show abnormal cognitive and social behavior».
Although the mutations of SETD5 gene represent the genetic cause of only a small portion of intellectual disabilities and autism cases, the mechanism identified could be common to other genes that perform similar tasks, as well as suggesting new research hypotheses: «Knowing the molecular mechanism behind a pathology is the first step to identify new possible therapeutic targets» Sessa concludes.
The research was funded by the Ministry of Health and the Telethon Foundation.
Alessandro Sessa, Luca Fagnocchi, Giuseppina Mastrototaro, Luca Massimino, Mattia Zaghi, Marzia Indrigo, Stefano Cattaneo, Davide Martini, Chiara Gabellini, Cecilia Pucci, Alessandra Fasciani, Romina Belli, Stefano Taverna, Massimiliano Andreazzoli, Alessio Zippo and Vania Broccoli, SETD5 regulates chromatin methylation state and preserves global transcriptional fidelity during brain development and neuronal wiring, Neuron, 9 September 2019