A study in mouse models and human tissue, carried out by researchers at the Barcelona Institute of Science and Technology Centre for Genomic Regulation (CRG), has found that the small nuceleolar RNA host gene, Snhg11, is less active in brains with Down syndrome (DS), potentially contributing to the memory deficits observed in people with the genetic disorder. The study indicated that Snhg11 is critical for the function and formation of neurons in the hippocampus, and offers up the first evidence that a noncoding RNA may play a critical role in the pathogenesis of DS. The results could help direct researchers to potential therapeutic strategies, the researchers suggested.

“There are many interventions to help people with Down syndrome live independently, but only few are pharmacological,” said Mara Dierssen, PhD, group leader of the cellular & systems neurobiology lab at the Centre for Genomic Regulation. “Studies like this help lay the foundations to find strategies that can help improve memory, attention, and language functions, or prevent cognitive decline associated with aging.” Dierssen and colleagues reported on their findings in a paper in Molecular Psychiatry, titled, “The lncRNA Snhg11, a new candidate contributing to neurogenesis, plasticity, and memory deficits in Down syndrome.”

Down syndrome is a genetic disorder caused by the presence of an extra copy of chromosome 21 (HSA21)—also known as trisomy 21—and is the most common genetic cause of intellectual disability, estimated to affect five million people globally, the authors wrote. People with DS have memory and learning problems, issues previously linked to abnormalities in the hippocampus, a part of the brain involved in learning and memory formation. “DS alters central nervous system development and function, impairing cognition, and adaptive behavior,” the team further noted. “Deficits in hippocampal-mediated learning and memory processes are hallmarks of DS, and molecular and cellular defects have been detected in post-mortem fetal DS hippocampus.”

DS is a disorder of gene expression deregulation, the investigators further explained, “… as the triplication of HSA21 results in a global disturbance of the transcriptome that is proposed to contribute to its phenotypic manifestations.” However, mechanisms that control gene expression are cell-type specific, and so understanding the full complexity of gene deregulation in DS may not be possible through bulk studies.

Traditionally, much of the focus in genomics has been on protein-coding genes, which in humans constitute around just 2% of the entire genome. The rest is “dark matter,” including vast stretches of noncoding DNA sequences that do not produce proteins but are increasingly recognized for their roles in regulating gene activity, influencing genetic stability, and contributing to complex traits and diseases.

Snhg11 is one gene found in this “dark matter.” It is a long noncoding RNA (lncRNA), a special type of RNA molecule that is transcribed from DNA but does not encode for a protein. Noncoding RNAs are important regulators of normal biological processes, and their abnormal expression has been previously linked to the development of human diseases, such as cancer. “In recent years, there has been a growing interest in lncRNAs, which have been shown to act as essential epigenetic regulators and have been functionally and mechanistically linked with neurobiological processes related to neuronal proliferation and differentiation and with learning and memory,” the team also stated.

And interestingly, they noted, a high number of lncRNAs are abnormally expressed in DS. The authors studied the hippocampus in the Ts65Dn mouse model, which has a genetic makeup similar to Down syndrome in humans. The hippocampus has many different cell types, and the team wanted to understand how the presence of an extra chromosome 21 affects these cells.

To carry out their study in the Ts65Dn mouse model, the researchers isolated nuclei from the brain cells in the hippocampus and used single nucleus RNA sequencing (snRNA-seq) to see which genes were active in each cell.  “… we used single nucleus RNA sequencing to dissect transcriptional dysregulation associated with specific cell types in the DS mouse model … we have generated the first single-nuclei atlas of a trisomic hippocampus by characterizing the transcriptome of tens of thousands of individual hippocampal neurons in parallel in the Ts65Dn mouse model of DS.”

The activity of Snhg11 (red) pictured in the dentate gyrus region of the hippocampus in mice.
The activity of Snhg11 (red) pictured in the dentate gyrus region of the hippocampus in mice. [Cesar Sierra/Centro de Regulación Genómica (CRG)]
One of the most striking findings was made in cells of the dentate gyrus, where the researchers detected an important reduction of the expression of Snhg11 which, they pointed out, is a lncRNA involved in cell proliferation in different types of cancer. The scientists subsequently validated some of their findings in another mouse model of DS, and in human postmortem DS brain tissue. They found lower levels of Snhg11 in the same types of tissues from human postmortem brains with trisomy 21, indicating the relevance for the human cases.

“Given the limitations of Ts65Dn, we validated the DG-specific downregulation of Snhg11 in an independent DS mouse model, the Dp16 … most importantly, in the dissected DG from human DS patients. Altogether, this indicates that Snhg11 deregulation is not limited to Ts65Dn and could constitute a common mechanism in DS.”

First author César Sierra, PhD, pointed out, “Snhg11 is particularly active in the dentate gyrus [DG], a part of the hippocampus crucial for learning and memory and one of the few brain regions where new neurons are continuously created throughout life. We found that abnormally expressed Snhg11 results in reduced neurogenesis and altered plasticity, which plays a direct role in learning and memory, thus indicating a key role in the pathophysiology of intellectual disability,”

To understand the effects of the reduced Snhg11 expression on cognition and brain function, the researchers then experimentally reduced the activity of the gene in the brains of healthy mice. “To elucidate the function of this long noncoding RNA (lncRNA), we knocked down Snhg11 in the DG of wild-type mice,” they wrote. They found that low levels of Snhg11 were sufficient to reduce synaptic plasticity, which is the ability for neuronal connections to strengthen or weaken over time. “Intriguingly, this intervention alone was sufficient to impair synaptic plasticity and adult neurogenesis, resembling the cognitive phenotypes associated with trisomy in the hippocampus,” they continued.

Synaptic plasticity is crucial for learning and memory. It also reduced the mouse’s ability to create new neurons. “We found that abnormally expressed Snhg11 results in reduced neurogenesis and altered plasticity, which plays a direct role in learning and memory, thus indicating a key role in the pathophysiology of intellectual disability,” Sierra further pointed out.

To understand the real-world impact of their findings, the researchers also conducted various behavior tests with mice. These experiments confirmed that low levels of Snhg11 led to similar memory and learning problems as seen in Down syndrome, suggesting the gene regulates brain function. “… the reduction of Snhg11 expression in the DG led to dramatic hippocampal-dependent memory deficit that recapitulate those observed in TS animals … We believe that the identification of Snhg11 as a key player in the DG constitutes an important contribution to support the involvement of lncRNAs in neuronal function and in neurodevelopmental disorders such as DS, highlighting their functional importance in synaptic plasticity, adult neurogenesis, and cognitive function,” the authors concluded.

Snhg11 has previously been linked to cell proliferation in different types of cancer. The researchers plan on carrying out 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 noncoding RNAs, many of which are yet to be discovered, might also contribute to intellectual disabilities.

The team concluded, “Given that lncRNAs represent a significant population of the human transcriptome, further research is warranted to investigate their role in DS.”

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