RNA molecule plays key role in cell dysfunction driving Rett: Study
NEAT1 regulation seen as potential treatment strategy
Dysfunction of an RNA molecule called NEAT1 contributes to nerve cell damage in Rett syndrome, a study suggested, implying that normalizing the activity of this molecule could be a viable treatment strategy for Rett.
The study, “NEAT1-mediated regulation of proteostasis and mRNA localization impacts autophagy dysregulation in Rett syndrome,” was published in Nucleic Acids Research. It was led by researchers at the Josep Carreras Leukaemia Research Institute.
RNA is a molecule that’s made when genes are activated or read. One kind of RNA is messenger RNA (mRNA), which serves as a template for the cellular machinery that makes new proteins. But there are other kinds of RNA molecules that have diverse functions within cells. One example is long-noncoding RNA, abbreviated lncRNA. As the name implies, these are large RNA molecules that don’t encode proteins, but play other roles in regulating cell activity.
Rett syndrome is caused mainly by mutations in the gene MECP2. The MECP2 gene is known to be important for regulating the activity of many other genes in cells, ultimately helping to control cell activities. In Rett syndrome, mutations in the MECP2 gene throw the normal regulatory functions into disarray, especially in nerve cells, which ultimately leads to disease symptoms. But while this general mechanism is well established, the details of how MECP2 mutations lead to dysregulation of cell activity aren’t fully understood.
Using cell models, researchers found that MECP2 mutations in young nerve cells lead to abnormally low levels of the lncRNA molecule NEAT1. Analyses of more mature brain tissue and of blood samples from people with Rett syndrome showed the opposite trend, with abnormally high levels of NEAT1. These findings imply that this RNA molecule is dysregulated in Rett syndrome, potentially with different effects depending on developmental stage and cell type, the researchers said.
Interactions and dysregulation
Further tests indicated that dysregulation of NEAT1 is closely linked to problems with a cellular process called autophagy. Derived from Greek words meaning self-eating, autophagy is basically a cellular recycling system that cells use to break up large molecules into smaller components that can then be repurposed and reused. In the cell models, problems with autophagy led to abnormal clumps of proteins in cells as well as problems with the function of mitochondria, which are cellular structures key for energy generation.
Digging a bit deeper, the researchers found that the NEAT1Â lncRNA is able to physically interact with mRNA molecules that are needed to make specific proteins involved in autophagy. This suggests a mechanism whereby MECP2 mutations lead to dysregulation of NEAT1, which in turn leads to abnormal processing of autophagy-related mRNAs, ultimately disrupting autophagy and causing cellular dysfunction.
“Altogether, these findings confirm NEAT1 as the primary mediator of MeCP2 [protein]Â regulation of autophagy-related genes,” the researchers wrote.
The data implied that if NEAT1 activity could be normalized, it might be possible to improve autophagy activity in Rett cells. Supporting this idea, the researchers found that, if they reactivated NEAT1 in cells harboring a MECP2 mutation, levels of autophagy-related proteins also increased.
The effects of reactivating NEAT1 weren’t limited to autophagy. Nerve cells carrying MECP2 mutations typically have fewer of the wire-like structures that nerves use to connect with each other — but when the researchers reactivated NEAT1, nerve cells developed more of these connective structures.
Collectively, these data suggest that dysregulation of the NEAT1 RNA molecule plays a key role in how MECP2 mutations dysregulate cell activity — and imply that normalizing NEAT1 activity may help to normalize nerve cell activity as a potential treatment strategy for Rett syndrome.
“Our findings underscore the potential therapeutic importance of targeting NEAT1 and autophagy as promising approaches to alleviate the molecular and cellular dysfunctions associated with [Rett syndrome],” the researchers wrote. “This offers hope for the development of novel treatment strategies for this debilitating neurodevelopmental disorder.”
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