Tushev, G., Glock, C., Heumueller, M., Biever, A., Jovanovic, M., and Schuman, E.M. (2018). Alternative 3’UTRs modify the localization, regulatory potential, stability, and plasticity of mRNAs in neuronal compartments. Neuron 98: 495-511
https://www.cell.com/neuron/abstract/S0896-6273(18)30236-8

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Our brain’s capacity to learn and to form memories relies on the ability to respond adaptively to environmental inputs. The integration of these inputs occurs at synapses, the connections between brain cells. Unlike other cell types in the body, neurons have an elaborate architecture, consisting of axons to transmit and dendrites to receive information. Like all cells, neurons use proteins to carry out their important cellular functions. Neurons supply their processes with proteins by moving mRNA molecules to the dendrites and axons where they can be locally translated.

A mRNA molecule consists of a coding sequence in the middle, which serves as a template for new proteins, and two non-coding regions located on both ends: the 3’ region on the right and 5’ on the left hand side. These so-called untranslated regions (UTRs) control gene expression at the RNA level and are variable in length and composition. By acting as binding platforms, they can regulate stability, trafficking and translation, thus dictating the fate of an mRNA molecule within a cell.

Researchers from the Schuman Lab now sequenced the mRNA present in different regions of rat hippocampal slices and took a closer look at the 3’ UTR region. Schuman: “When we examined mRNA in both neuronal cell bodies and in the neuropil, primarily consisting of axons and dendrites, we noticed a huge diversity in the 3’UTRs of neuronal mRNAs with many transcripts showing enrichment for a particular 3’UTR isoform in a cellular compartment. In addition, the isoforms enriched in the neuropil proved to be more stable than those located in the cell body.” The scientists were even able to follow the dynamics of these molecules during a period of enhanced neural activity and observed an alteration of 3’UTR isoforms present in each compartment. The Schuman team speculates that some of the changes in the dendritic compartment might be due to local remodeling of 3’UTRs.

Tushev, G., Glock, C., Heumueller, M., Biever, A., Jovanovic, M., and Schuman, E.M. (2018). Alternative 3’UTRs modify the localization, regulatory potential, stability, and plasticity of mRNAs in neuronal compartments. Neuron 98: 495-511
https://www.cell.com/neuron/abstract/S0896-6273(18)30236-8

The post Non-coding RNA reveals its secrets first appeared on Max Planck Neuroscience.

The human genome is made up of ~3 billion letters of DNA and at each position, it is possible to have different letters, called variants. Some variants are harmless but others can be detrimental, making it a mammoth task to find out which variants cause a disorder. Researchers often choose to search only the 1-2% of the genome that carries the information to make proteins. While this has been successful for a few disorders, most neurodevelopmental disorders are still largely unexplained, making it clear that looking elsewhere in the genome is necessary.

“The remaining 98% of the genome offers a lot of untapped potential to find changes that can cause disorders” Paolo Devanna, co-author of the study explains. “These parts of the genome are known as ‘non-coding’, but that doesn’t mean that they are not important. They have very vital jobs to do, for example, to control when, where and how much protein is made. So if this process gets messed up, it could have severe consequences, like neurodevelopmental disorders.” For this reason, Devanna and his colleagues decided to look at the so-called 3’UTRome. This is a part of the non-coding genome that regulates how much protein is made.

Searching for causes of language impairment

To test this approach, the researchers looked at the DNA of children with severe language problems and identified genetic variants in the 3’UTRome. “Language disorders are a very complex neurodevelopmental disorder and finding their genetic causes has been particularly challenging – we have only a small number of candidate genes thus far,” said Dr Sonja Vernes who led the study. She runs a research group at the Max Planck Institute for Psycholinguistics and is part of the Donders Institute for Brain, Cognition and Behaviour at the Radboud University, both in Nijmegen, the Netherlands.

The researchers tested the impact of each 3’UTRome variant on the expression of the candidate genes for languages impairment. One of the variants has a significant effect on the expression of a gene known as ARHGEF39. “If a cell carries this single letter change in the 3’UTRome, they express more ARHGEF39. We were very excited by this finding because this is the first time we have found a variant associated with specific language impairment that we can show has a clear biological effect” said Devanna. “Having too much of a protein at important points in development could affect how neurons and neuronal circuits develop and function, which could, in turn, could affect how children develop their language skills” Vernes explains.

The researchers were able to find the specific gene variants, which seem to contribute to language impairment, through collaboration with the UK Specific Language Impairment Consortium.

Non-coding variants are widespread in genetic disorders

Given this success, the researchers went on to explore the 3’UTRome in other neurodevelopmental disorders. They identified 25 further genetic changes in the DNA of individuals with autism, schizophrenia and bipolar disorder that are thought to control protein levels in the same way. “We are tapping into a new and promising source of genetic variation,” Vernes said. “Our study shows that the identification and testing of non-coding variants will foster our understanding of the genetic causes of neurodevelopmental disorders, which is crucial in the long term for the design of new and effective therapeutics.”

Neurodevelopmental disorders (NDDs) like schizophrenia, autism and bipolar disorders encompass a wide range of disabilities associated with the functioning of the brain. Severe NDDs are currently known to affect approximately 5% of the population, making understanding their causes and in turn, their possible treatments an important area of study.

Original Publication:
Devanna, P., Chen, X.S., Ho, J., Gajewski, D., Smith, S.D., Gialluisi, A., Francks, C., Fisher, S.E., Newbury, D.F., & Vernes, S.C. (2017). Next-gen sequencing identifies non-coding variation disrupting miRNA binding sites in neurological disorders. Molecular Psychiatry. DOI: https://doi.org/10.1038/mp.2017.30

The post Defect in non-coding DNA might trigger brain disorders such as severe language impairment first appeared on Max Planck Neuroscience.