Circular RNAs Identified in Brain Cells Impaired by Alzheimer’s, Parkinson’s

“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, MD, of the Department of Neurology and the American Parkinson Disease Association Center for Advanced Parkinson Research at Brigham. “We found that these circular RNAs were produced in large quantities by brain cells, including those associated with Parkinson’s and Alzheimer’s.” Scherzer is corresponding author of the team’s published paper in Nature Communications, titled “Circular RNAs in the human brain are tailored to neuron identity and neuropsychiatric disease,” in which they concluded, “Based on these and prior data, we hypothesize that circRNAs may serve as finely tuned, special-purpose RNA vehicles for the assembly of cell type-specific synapses and that their dysregulation may contribute to synaptopathies … More generally, this study provides a unique catalog of circRNAs in two major types of human brain neurons that will be generally useful for decoding genome function in neuropsychiatric disease and for advancing the burgeoning field of RNA medicines and diagnostics.”

Circular RNAs are prominently enriched in synapses and brain, and are linked to neuronal development and aging, the authors noted. However,they continued, while circRNAs have been linked to peripheral diseases, and particularly cancer, “… their role in brain health is largely unexplored, with initial clues pointing at a role in neurodegenerative diseases and psychiatric diseases.” Intriguingly, the team continued, one study has suggested that circRNAs may display cell-specific expression patterns in inhibitor and excitatory neurons.

For their newly reported study Scherzer and colleagues laser-captured neurons from 190 frozen postmortem human brain samples, including some non-neuronal cells for comparison. Then, they used ultra-deep, total RNA sequencing to study the exact sequences of genetic code found in the circular RNAs within these two cell types.

They discovered that 61 percent of all synaptic circRNAs they characterized were associated with brain disorders. Notably, they found 4,834 cell-type specific circular RNAs in dopamine and pyramidal neurons, two highly functioning brain cells. “1526 and 3308 circRNAs are custom-tailored to the cell identity of dopamine and pyramidal neurons and enriched in synapse pathways,” the investigators stated. “29% of Parkinson’s and 12% of Alzheimer’s disease-associated genes produced validated circRNAs.” Dopamine neurons control movement, mood, and motivation while pyramidal neurons 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 the first author Xianjun Dong, PhD, an assistant professor in the Department of Neurology and the Genomics and Bioinformatics Hub at the Brigham. “circRNA diversity provides finely tuned, cell type-specific information that is not explained by the corresponding linear RNAs from the same gene.” And as the authors pointed out, “The fact that circRNAs are predominantly expressed from synapse loci in human dopamine and pyramidal neurons raises the possibility that they encode as yet unknown important functions in synaptic functions of the human neuronal networks controlling quintessential human experiences: fine motor movements, motivation, reward, and higher cortical functions.”

Degeneration of dopamine and pyramidal neurons plays a key role in the development of neurological disorders. When the researchers investigated this connection with circRNAs further, they found that a surprising number of Parkinson’s and Alzheimer’s genes produced circular RNA. For example, expression of one circRNA produced from the Parkinson’s gene DNAJC6 was reduced in vulnerable dopamine neurons even prior to symptom onset.

The team also discovered that genes associated with different diseases produced circRNAs in particular cell types. “Disease-linked circRNAs expression showed, in part, evidence of cell type bias,” they wrote. “Addiction-associated genes prominently express circRNAs in dopamine neurons, autism genes express circRNAs predominantly in pyramidal neurons, and interestingly, PD GWAS-associated loci express circRNAs highly in nonneuronal cells as well as in neurons.”

Limitations of the team’s study include an incomplete understanding of how this complex RNA machinery specifies neuron and synapse identity. Future research might investigate how these circRNAs arise and function and survey additional genetic regulators that govern their behavior. As the team commented, “Much more work will be required to fully elucidate the kinetics and relation of circular and cognate linear RNA biogenesis, the involved regulators, and to reveal how this complex RNA machinery specifies neuron identity and synapses.”

Nevertheless, the newly reported findings provide what the team claims is the most comprehensive analysis of circRNAs in human brain cells to-date, and suggest they can be leveraged for RNA diagnostics and medicines used to treat neurological conditions.

“Naturally occurring circRNAs have the potential to serve as biomarkers for specific brain cells implicated in early, prodromal stages of a disease,” Scherzer said. “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.” Added 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.”