Researchers have gained new insights into a largely overlooked circular RNA in brain cells and the key role it plays in diseases such as Alzheimer's and Parkinson's. In addition to providing valuable information about the molecular mechanisms of these diseases, their findings open the door to the development of diagnostic tests and treatments.
Unlike linear RNA, circular RNA (circRNA) has a closed-loop structure without free ends. Scientists have long dismissed circular ribonucleic acids (circRNAs) as having little impact, and only recently have they been studied in depth, particularly for their role in brain health.
In a new study, researchers at Brigham and Women's Hospital in Boston identified and cataloged these mysterious circRNAs and found that they are associated with brain cell properties and the neurodegenerative diseases Alzheimer's and Parkinson's.
Clemens Scherzer, corresponding author of the study, said: "Circular RNA has long been dismissed as junk, but we believe it plays an important role in the programming of human brain cells and synapses. We found that these circular RNAs are produced in large quantities in brain cells, including those associated with Parkinson's and Alzheimer's diseases."
The researchers collected neuronal and non-neuronal cells (for comparison) from 190 postmortem human brains and used total RNA sequencing to map the genetic code in the cells' circular RNAs.
They found that 61% of synaptic circRNAs were associated with brain diseases. Notably, they observed 4834 circRNAs customized according to the cellular properties of dopamine neurons and pyramidal neurons and enriched in synaptic pathways. Dopamine neurons in the midbrain control movement, emotion, and motivation, while pyramidal neurons in the temporal cortex play important roles in memory and language.
"Surprisingly, it is the circular RNAs rather than the linear RNAs produced by these gene locations that determine neuron identity," said Dong Xianjun, first author of the study. "Circular RNA diversity provides finely tuned cell type-specific information that cannot be explained by the corresponding linear RNAs from the same gene."
It is known that the degeneration of dopamine and pyramidal neurons plays a role in the development of neurological diseases. After digging deeper, the researchers found that 29% of Parkinson's disease and 12% of Alzheimer's disease-related genes produced circRNA. They found that the expression of a special circRNA produced by the Parkinson's disease gene DNAJC6 in dopamine neurons was reduced before symptoms appeared.
Globally, they found that genes associated with different disease states produce circRNA. Addiction-related genes preferentially produce circRNA in dopamine neurons, autism-related genes produce circRNA in pyramidal neurons, and cancer produces circRNA in non-neuronal cells.
Their findings highlight the potential use of circRNAs. "Naturally occurring circRNAs have the potential to serve as biomarkers for specific brain cells, associated with early, prodromal stages of disease," Scherzer said. "Circular RNAs are not easily broken down, making them a powerful reporting tool and therapeutic. They can be synthetically rewritten and used as future digital RNA medicines."
Current research does not yet fully understand how this complex RNA machinery specifies neuronal and synaptic identity. Further research is needed on how circRNAs function and the genetic regulators that govern their behavior.
However, this study provides the most comprehensive analysis of circulating RNA in human brain cells to date.
"The discovery of circular RNAs has changed our understanding of the molecular mechanisms underlying neurodegenerative diseases," Dong said. "Circular RNAs are more durable than linear RNAs and have potential as RNA therapeutics and RNA biomarkers."
The research was published in the journal Nature Communications.