Researchers at the Centre for Genomic Regulation (CRG) have unveiled the critical role of the Snhg11 gene in the function and formation of neurons in the hippocampus. Through experiments with mice and human tissues, it was discovered that the gene is less active in brains with Down syndrome, potentially contributing to the memory deficits observed in individuals with the condition. These groundbreaking findings have been published in the journal Molecular Psychiatry.
Traditionally, genomics has primarily focused on protein-coding genes, which make up only about 2% of the entire human genome. The remaining “dark matter” consists of extensive non-coding DNA sequences that do not produce proteins but are now recognized for their roles in regulating gene activity, influencing genetic stability, and contributing to complex traits and diseases.
Snhg11 is one of the genes found in this “dark matter.” It is a long non-coding RNA, a special type of RNA molecule that is transcribed from DNA but does not encode a protein. Non-coding RNAs play crucial roles in normal biological processes, and their abnormal expression has been linked to the development of diseases like cancer. This study provides the first evidence that a non-coding RNA like Snhg11 plays a crucial role in the pathogenesis of Down syndrome.
Down syndrome is a genetic disorder caused by the presence of an extra copy of chromosome 21, also known as trisomy 21. It is the most common genetic cause of intellectual disability, affecting an estimated five million individuals worldwide. People with Down syndrome experience memory and learning difficulties, which have been previously associated with abnormalities in the hippocampus, a brain region involved in learning and memory.
Snhg11 is particularly active in the dentate gyrus, a critical part of the hippocampus responsible for learning and memory and where new neurons are continuously generated throughout life. Abnormal Snhg11 expression leads to reduced neurogenesis and altered plasticity, directly impacting learning and memory function, highlighting its key role in the pathophysiology of intellectual disability. Dr. César Sierra, the first author of the paper, emphasized these findings.
The researchers conducted studies on mouse models with genetic similarities to Down syndrome to understand how the presence of an extra chromosome 21 affects different cell types in the hippocampus. They isolated nuclei from brain cells and used single nucleus RNA sequencing to determine gene activity in each cell. A significant reduction in Snhg11 expression was observed in cells of the dentate gyrus, with similar findings in postmortem brain tissues from individuals with trisomy 21, underscoring the relevance of these results for human cases.
To investigate the impact of reduced Snhg11 expression on cognition and brain function, the researchers experimentally decreased the gene’s activity in healthy mice brains. This led to decreased synaptic plasticity, essential for learning and memory, as well as reduced neurogenesis. Behavior tests with mice further confirmed that low levels of Snhg11 resulted in memory and learning impairments akin to those seen in Down syndrome, highlighting the gene’s role in regulating brain function.
Previous research has linked Snhg11 to cell proliferation in various cancers. The researchers plan to delve deeper into the mechanisms underlying its actions, potentially paving the way for new therapeutic interventions. They also aim to explore other long non-coding RNA genes that may contribute to intellectual disabilities, offering new avenues for research and potential treatments.
Dr. Mara Dierssen, co-author of the paper and Group Leader of the Cellular & Systems Neurobiology lab at the Centre for Genomic Regulation, highlighted the importance of studies like this in laying the groundwork for strategies to improve memory, attention, language functions, and prevent cognitive decline associated with aging in individuals with Down syndrome.
