April 13, 2024

Link discovered between the “dark matter” of the genome and the mystery of Down syndrome

Researchers at the Center for Genomic Regulation have discovered the critical role of the Snhg11 gene in the function and formation of neurons in the hippocampus, linking its reduced activity to memory deficits in Down syndrome. This study, which uses mouse models and human tissue analysis, marks a significant step in understanding the genetic basis of Down syndrome by focusing on the largely unexplored “dark matter” of the genome. The research highlights the potential of targeting long noncoding RNAs, such as Snhg11, for the development of novel therapeutic interventions aimed at improving cognitive functions in individuals with Down syndrome.

The intellectual disability observed in individuals with three copies of chromosome 21 can be attributed to reduced activity of the Snhg11 gene in the brain.

Scientists at the Center for Genomic Regulation (CRG) discovered the significant role of the Snhg11 gene in the development and functionality of hippocampal neurons. Experiments involving mice and human samples have shown reduced activity of this gene in brains affected by Down syndrome, suggesting a link to the memory challenges faced by individuals with the syndrome. The findings were recently published in the journal Molecular Psychiatry.

Traditionally, much of the focus in genomics has been on protein-coding genes, which in humans constitute only about 2% of the entire genome. The rest is “dark matter,” including vast expanses of uncoded matter SNHG11 Expression in the Hippocampus

Snhg11 activity (red) depicted in the dentate gyrus region of the hippocampus in mice. Credit: Cesar Sierra/Center for Genomic Regulation (CRG)

The researchers isolated the nuclei of brain cells and used a technique called single-nucleus RNA sequencing to see which genes are active in each cell. One of the most striking discoveries was in cells of the dentate gyrus, where researchers detected a significant reduction in the expression of Snhg11. The researchers also found lower levels of Snhg11 in the same tissue types from human trisomy 21 post-mortem brains, indicating relevance to human cases.

To understand the effects of reduced Snhg11 expression on cognition and brain function, researchers experimentally reduced the gene’s activity in the brains of healthy mice. They found that low levels of Snhg11 were sufficient to reduce synaptic plasticity, which is the ability of neuronal connections to strengthen or weaken over time. Synaptic plasticity is crucial for learning and memory. It also reduced the mouse’s ability to create new neurons.

Future Directions and Potential Therapies

To understand the real-world impact of their findings, the researchers also performed several behavioral tests on rats. These experiments confirmed that low levels of Snhg11 led to memory and learning problems similar to those seen in Down syndrome, suggesting that the gene regulates brain function.

Snhg11 has already been associated with cell proliferation in different types of cancer. The researchers plan to conduct further research to discover the exact mechanisms of action involved, information that could open potential avenues for new therapeutic interventions. They will also explore whether other genes involving long non-coding RNAs, many of which have not yet been discovered, may also contribute to intellectual disabilities.

“There are many interventions to help people with Down syndrome live independently, but only some are pharmacological. Studies like this help lay the groundwork for finding strategies that can help improve memory, attention and language functions, or prevent cognitive decline associated with aging,” says Dr. Mara Dierssen, co-author of the paper and leader of the Cellular group & Systems Neurobiology Laboratory of the Center for Genomic Regulation.

Reference: “The lncRNA Snhg11, a novel candidate that contributes to neurogenesis, plasticity and memory deficits in Down syndrome” by Cesar Sierra, Miguel Sabariego-Navarro, Álvaro Fernández-Blanco, Sonia Cruciani, Alfonsa Zamora-Moratalla, Eva Maria Novoa and Mara Dierssen, February 27, 2024, Molecular Psychiatry.
DOI: 10.1038/s41380-024-02440-9

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