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  • New Research on Circular RNAs Points to Potential Neurological Disease Biomarkers

    Recent research focused on circular RNAs (circRNAs) in brain cells offers fresh perspectives on neurological diseases, particularly Parkinson’s and Alzheimer’s disease. A team from Brigham and Women’s Hospital discovered more than 11,000 distinct RNA circles characterizing brain cells implicated in these two major diseases. Their findings are now available in Nature Communications.

    In the past, the scientific community often regarded circular RNA as inconsequential genetic "junk." However, Clemens Scherzer, MD, emphasized, “We found that these circular RNAs were produced in large quantities by brain cells, including those associated with Parkinson’s and Alzheimer’s.”

    For this study, the team procured neurons from 190 frozen postmortem human brain samples, alongside some non-neuronal cells. Utilizing ultra-deep, total RNA sequencing, they analyzed the genetic code sequences present in the circRNAs of these cells.

    In their analysis, they determined that a significant portion of all synaptic circRNAs they profiled related to brain disorders. Interestingly, many were found in dopamine and pyramidal neurons, critical brain cells responsible for movement, mood, motivation, memory, and language. Xianjun Dong, PhD, remarked, “It was surprising that the circular RNAs rather than the linear RNAs produced from these gene locations defined neuron identity. circRNA diversity provides finely tuned, cell type-specific information that is not explained by the corresponding linear RNAs from the same gene.”

    This research underscores the significance of dopamine and pyramidal neurons in neurological disorder development. A closer look revealed that numerous genes associated with Parkinson's and Alzheimer's diseases produced circular RNA. For instance, a circRNA from the Parkinson’s gene DNAJC6 showed reduced expression in dopamine neurons even before symptoms manifested.

    Scherzer further highlighted the potential benefits of these findings, stating, “Naturally occurring circRNAs have the potential to serve as biomarkers for specific brain cells implicated in early, prodromal stages of a disease. Circular RNAs cannot easily be broken down, making them a powerful tool as reporters and for delivering therapies. They could be rewritten synthetically and harnessed as future digital RNA medicines.”

    Furthermore, the research team found a link between specific disease-associated genes and the circRNAs they produce in particular cell types. Examples include addiction-associated genes producing circRNAs in dopamine neurons and autism-associated genes in pyramidal neurons.

    However, a complete understanding of the intricate RNA machinery remains elusive. The team looks forward to investigating the origins and functionalities of these circRNAs further.

    Concluding on a note of optimism, Dong said, “The discovery of circular RNAs changes our understanding of the molecular mechanisms behind neurodegenerative disorders. Circular RNAs are much more durable than linear RNAs and hold promise as RNA therapies and RNA biomarkers.”

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