Unveiling the Enigmatic RNA Circles Formed by Compromised Cells in Parkinson’s and Alzheimer’s Disease

New insights into neurological diseases are emerging as researchers delve into the world of circular RNAs (circRNAs) within brain cells. A recent study conducted by investigators at Brigham and Women’s Hospital, a key member of the Mass General Brigham healthcare system, has unveiled a trove of over 11,000 distinct RNA circles that define brain cells linked to conditions like Parkinson’s disease and Alzheimer’s disease. These groundbreaking findings are set to be published in the journal Nature Communications on September 18th.

For this study, Dr. Clemens Scherzer and his team employed advanced techniques to capture neurons from 190 frozen postmortem human brain samples, which included non-neuronal cells for reference. Through ultra-deep, total RNA sequencing, they meticulously examined the precise genetic sequences within circRNAs in these two types of cells.

A remarkable discovery was made, revealing that 61% of all synaptic circRNAs identified were associated with various brain disorders. Intriguingly, the researchers pinpointed 4,834 cell-specific circRNAs within dopamine and pyramidal neurons, both highly specialized brain cells. Dopamine neurons, responsible for controlling movement, mood, and motivation, were found to produce circRNAs, as did pyramidal neurons, which play crucial roles in memory and language.

The most surprising revelation was that these circular RNAs, rather than their linear counterparts, defined the identity of these neurons. Dr. Xianjun Dong, the first author of the study, emphasized that circRNA diversity offers finely-tuned, cell-specific information not mirrored by linear RNAs from the same genes.

Furthermore, the researchers explored the connection between the degeneration of dopamine and pyramidal neurons and the development of neurological disorders. They discovered that a significant number of genes associated with Parkinson’s and Alzheimer’s disease produced circular RNAs. For instance, a circRNA produced from the Parkinson’s gene DNAJC6 exhibited reduced expression in vulnerable dopamine neurons even before symptoms appeared.

Dr. Scherzer highlighted the potential of naturally occurring circRNAs as biomarkers for specific brain cells implicated in the early stages of diseases. Their resilience against degradation makes them potent tools for diagnostics and therapeutic delivery, potentially serving as the foundation for future RNA-based medicines.

The study also shed light on how genes related to different diseases produced circRNAs in specific cell types. Addiction-related genes generated circRNAs in dopamine neurons, autism-related genes in pyramidal neurons, and cancer-associated genes in non-neuronal cells.

Although the study has some limitations, such as an incomplete understanding of the complex RNA machinery governing neuron and synapse identity, it represents the most comprehensive analysis of circRNAs in human brain cells to date. These findings suggest that circRNAs hold significant promise for RNA diagnostics and therapies aimed at treating neurological conditions.

In the words of Dr. Dong, “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.”

This groundbreaking research received partial funding from the American Parkinson Disease Association, NIH, and the U.S. Department of Defense, with additional contributions from the ASAP Foundation. Dr. Scherzer has had affiliations with various pharmaceutical and research organizations, and Dr. Dong’s work has been supported by NIH, APDA, and ASAP.

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