Researchers have gained new insights into largely overlooked circular RNAs in brain cells and the crucial role they play in diseases like Alzheimer’s and Parkinson’s. In addition to providing valuable information about the molecular mechanisms underlying these conditions, their findings open the door to developing diagnostic tests and treatments for them.
Unlike their linear counterparts, circular RNAs (circRNAs) have a closed-loop structure and lack free ends. Long dismissed by scientists as being of little consequence, circRNAs have remained largely unexplored until recently, especially in regards to their role in brain health.
In a new study, researchers from Brigham and Women’s Hospital in Boston have identified and catalogued these mysterious circRNAs and found that they’re linked to brain cell identity and the neurodegenerative disorders Alzheimer’s and Parkinson’s diseases.
“Circular RNA has long been cast aside as junk, but we believe it has an important role in programming human brain cells and synapses,” said Clemens Scherzer, corresponding author of the study. “We found that these circular RNAs were produced in large quantities by brain cells, including those associated with Parkinson’s and Alzheimer’s.”
The researchers collected neurons and non-neuronal cells (for comparison) from 190 postmortem human brains and used total RNA sequencing to map the genetic code in the cells’ circRNAs.
They found that 61% of all synaptic circRNAs were associated with brain disorders. Notably, they observed that 4,834 circRNAs were custom-tailored to the cell identity of dopamine and pyramidal neurons and were enriched in synapse pathways. Dopamine neurons in the midbrain control movement, mood, and motivation, whereas pyramidal neurons in the temporal cortex play an important role in memory and language.
“It was surprising that the circular RNAs rather than the linear RNAs produced from these gene locations defined neuron identity,” said Xianjun Dong, the study’s lead author. “circRNA diversity provides finely tuned, cell type-specific information that is not explained by the corresponding linear RNAs from the same gene.”
Degeneration of dopamine and pyramidal neurons is known to play a role in the development of neurological disorders. Looking deeper, the researchers found that 29% of Parkinson’s and 12% of Alzheimer’s disease-associated genes produced circRNA. They found that the expression of one particular circRNA produced by the Parkinson’s gene DNAJC6 was reduced in dopamine neurons prior to the onset of symptoms.
Globally, they found that circRNAs are produced by genes associated with different disease states. Addiction-associated genes preferentially produced circRNAs in dopamine neurons, autism-associated genes in pyramidal neurons, and cancers in non-neuronal cells.
The researchers say their findings highlight the potential uses for circRNA.
“Naturally occurring circRNAs have the potential to serve as biomarkers for specific brain cells implicated in early, prodromal stages of a disease,” said Scherzer. “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.”
The current study was unable to provide a complete understanding of how this complex RNA machinery specifies neuron and synapse identity. Further research is needed to investigate how circRNAs function and the genetic regulators that govern their behavior.
Nevertheless, the study has provided the most comprehensive analysis of circRNAs in human brain cells to date.
“The discovery of circular RNAs changes our understanding of the molecular mechanisms behind neurodegenerative disorders,” Dong said. “Circular RNAs are much more durable than linear RNAs and hold promise as RNA therapies and RNA biomarkers.”
The study was published in the journal Nature Communications.
Source: Brigham and Women’s Hospital