Mysterious Circular RNA Linked to Alzheimer’s and Parkinson’s Diseases
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Scientists Uncover Mysterious Circular RNA Linked to Alzheimer’s and Parkinson’s Diseases
Researchers have gained new insights into the largely overlooked world of circular RNA (circRNA) in brain cells and its crucial role in diseases like Alzheimer’s and Parkinson’s.
In addition to shedding light on the molecular mechanisms of these diseases, their findings open doors to diagnostic tests and potential treatments.
Different from linear RNA, circRNA possesses a closed-loop structure with no free ends. For a long time, scientists believed that circular ribonucleic acid (circRNA) had minimal impact until recently when they delved deeper into its role, especially in brain health.
In a new study, researchers at Brigham and Women’s Hospital in Boston identified and cataloged these enigmatic circRNAs, revealing their associations with brain cell characteristics and neurodegenerative diseases like Alzheimer’s and Parkinson’s.
Clemens Scherzer, the corresponding author of the study, stated, “Circular RNA has long been considered as genetic ‘junk,’ but we believe it plays a significant role in the programming of human brain cells and synapses. We found that these circular RNAs are highly abundant in brain cells, including those related to Parkinson’s and Alzheimer’s.”
The researchers collected neurons and non-neuronal cells from 190 postmortem human brains for comparison and used total RNA sequencing to decipher the genetic code within cell circular RNA.
They found that 61% of synaptic circRNA was linked to brain diseases. Notably, they observed that 4,834 circRNAs were customized based on the cell characteristics of dopamine neurons and pyramidal neurons and were enriched in synaptic pathways. Dopamine neurons in the midbrain control movement, emotion, and motivation, while pyramidal neurons in the temporal lobe cortex play a vital role in memory and language.
The study’s first author, Xianjun Dong, remarked, “Surprisingly, it’s these circRNAs generated from specific gene locations, rather than linear RNAs, that determine the identity of neurons. CircRNA diversity provides finely tuned cell-type-specific information that linear RNAs from the same genes cannot explain.”
It is well-known that the degeneration of dopamine and pyramidal neurons plays a role in the development of neurological diseases. Upon further investigation, the researchers found that 29% of Parkinson’s disease-related genes and 12% of Alzheimer’s disease-related genes produced circRNA. They discovered that a specific circRNA produced by the Parkinson’s disease gene DNAJC6 had reduced expression in dopamine neurons before symptoms appeared.
On a global scale, they found that genes associated with different disease states generated circRNA. Addiction-related genes predominantly produced circRNA in dopamine neurons, autism-related genes produced circRNA in pyramidal neurons, and cancer genes produced circRNA in non-neuronal cells.
Their findings highlight the potential utility of circRNA. Scherzer stated, “Naturally occurring circRNA could serve as biomarkers for specific brain cell types, associated with early or prodromal stages of diseases. Circular RNA is resistant to degradation, making it a powerful reporting tool and therapeutic agent. They can be synthesized and repurposed for future digital RNA medicines.”
Currently, research has not fully elucidated how this intricate RNA mechanism specifies neuron and synaptic identities. Further research is needed to understand how circRNA functions and the genetic regulatory factors governing its behavior.
Nevertheless, this study provides the most comprehensive analysis to date of circular RNA in human brain cells.
“The discovery of circular RNA changes our understanding of the molecular mechanisms behind neurodegenerative diseases,” Dong said. “Circular RNA holds promise as an RNA therapy and RNA biomarker, being more durable than linear RNA.”
The study was published in the journal Nature Communications.
Mysterious Circular RNA Linked to Alzheimer’s and Parkinson’s Diseases
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