They discover a key gene for memory and learning deficits in Down syndrome

A team from the Center for Genomic Regulation (CRG) reveals that the gene Snhg11 It is important for the function and formation of neurons in the hippocampus. Experiments with mice and human tissue show that the gene is less active in brains with Down syndrome, which could contribute to this Memory deficits observed in people who have the genetic change. The results are published today in the specialist journal Molecular Psychiatry.

Much of the attention in genomics has focused on protein-coding genes, which in humans make up about 2% of the entire genome. But the “hidden side” of the genome includes many non-coding DNA sequences whose roles in regulating gene activity, affecting genetic stability, and contributing to complex traits and diseases such as Snhg11 are increasingly recognized.

This is a special type of RNA that is transcribed from DNA but does not result in the synthesis of a protein. This study is the first evidence that a non-coding RNA plays a critical role in the pathogenesis of Down syndrome, a genetic disorder caused by the presence of an extra copy of chromosome 21, also known as Down syndrome Trisomy 21.

Abnormal expression of Snhg11 leads to reduced neurogenesis and impaired plasticity, which plays a direct role in learning and memory. This suggests that the gene plays a key role in the pathophysiology of intellectual disability.

Cesar Sierra (CRG)

Is the most common genetic cause of intellectual disabilityIt is estimated that five million people worldwide are affected. People with Down syndrome have memory and learning problems that result from abnormalities in the hippocampus, a part of the brain involved in learning and memory formation.

“The gene is particularly active in the dentate gyrus, one of the few regions of the brain in which new neurons are continually created throughout life. We found that the abnormal expression of Snhg11 “This leads to reduced neurogenesis and impaired plasticity, which plays a direct role in learning and memory, and suggests that the gene plays a key role in the pathophysiology of intellectual disability,” he says. Cesar SierraFirst author of the article.

How low Snhg11 levels affect

The team examined the hippocampus in mouse models that have similar genetic makeup to Down syndrome in humans. The hippocampus is made up of many different cell types, and the study aimed to understand how the presence of an extra chromosome affects these cells.

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They isolated nuclei from 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 findings occurred in the cells of the dentate gyrus, where a significant reduction in expression was noted Snhg11. They also found lower values Snhg11 in the same tissue types from human brains with trisomy 21 obtained from postmortem donors.

The study authors will conduct further research to uncover the mechanisms of action involved, information that could open potential avenues for new therapeutic interventions.

The experts then reduced the activity of the gene in the brains of healthy mice and found that low levels of Snhg11 were sufficient to reduce synaptic plasticity, i.e. 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.

To understand the real-world implications of their findings, the researchers also conducted several behavioral tests on mice. These experiments confirmed that low concentrations of Snhg11 led to memory and learning problems similar to those of Down syndrome, suggesting that the gene regulates brain function. Before this work is the activity of Snhg11 It has only been linked to cell proliferation in various types of cancer.

Pathways for new therapeutic interventions

The study authors will conduct further research to discover the mechanisms of action involved, information that could open potential avenues for new therapeutic interventions. They will also investigate whether other genes with long non-coding RNAs, many of which have yet to be discovered, could also contribute to intellectual disability.

“There are many interventions to help people with Down syndrome live independently, but few are pharmacological. “Studies like this help lay the foundation for the search for strategies that improve memory, attention and language functions or prevent the cognitive decline that comes with age,” he concludes. Mara DierssenLead author of the study.

Reference:

Sierra et al. Molecular Psychiatry2024.

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