Circular RNA, once viewed as cell ‘junk,’ may influence Parkinson’s
Study finds over 1,500 circRNAs 'highly produced' by dopaminergic neurons
Dopamine-making neurons — whose loss characterizes Parkinson’s disease — produce thousands of circular RNA molecules that, beyond their normal duties, may play a role in neurodegenerative diseases, a study reports.
“Circular RNA has long been cast aside as junk, but we believe it has an important role in programming human brain cells and synapses,” Clemens Scherzer, MD, the study’s senior author at Harvard Medical School’s Brigham and Women’s Hospital, in Boston, said in a hospital press release.
Synapses are the point of near contact between nerve cells, where they release electrical or chemical signals that allow cells to communicate with each other.
“We found that these circular RNAs were produced in large quantities by brain cells, including those associated with Parkinson’s and Alzheimer’s,” added Scherzer, who is the director of Brigham’s Center for Advanced Parkinson Research.
The study, “Circular RNAs in the human brain are tailored to neuron identity and neuropsychiatric disease,” was published in Nature Communications and partly supported by the American Parkinson Disease Association.
Role of circular RNAs in brain health ‘largely unexplored,’ scientists say
When a gene is ‘read,’ the genetic code is copied from a cell’s DNA into another molecule called RNA. The RNA then can be used as a template to make proteins, or it can have other regulatory activities inside a cell.
While most RNA research has focused on linear molecules that form long ribbon-like strands, much less is known about the RNA strands that curl up to form circular structures, referred to as circular RNA or circRNA.
These circular RNAs long have been dismissed as molecular junk, but increasing research is revealing that they play a role in regulating cell activities and gene and protein activity, while in some cases also being used as protein templates.
CircRNAs have been linked to diseases such as “cancer, but their role in brain health is largely unexplored with initial clues pointing at a role in neurodegenerative diseases and psychiatric diseases,” the researchers wrote.
Scherzer and colleagues conducted detailed analyses of circRNA molecules in cells from nearly 200 brain samples, including those from people with Parkinson’s or Alzheimer’s as well as from people with no neurological disease.
The scientists specifically analyzed the circRNA makeup inside of three cell types: dopamine-producing neurons, pyramidal neurons, and non-neuron cells.
Dopamine-producing, or dopaminergic, neurons are progressively lost in people with Parkinson’s, causing the disease’s hallmark symptoms. These cells were collected from healthy adults serving as controls, Parkinson’s patients, and people with prodromal Parkinson’s.
Prodromal Parkinson’s refers to an early disease stage, in which people show molecular and/or brain features of the disease and possibly some symptoms, but not those considered classic hallmarks of Parkinson’s.
Pyramidal neurons, which are involved in memory, were collected from healthy controls and people with Alzheimer’s, a neurodegenerative disease characterized by memory deficits and cognitive impairment.
Across all the cell types, the scientists confirmed the identity of more than 11,000 unique circRNA molecules.
In many cases, a single gene could produce multiple circRNA molecules. For example, an Alzheimer’s-associated gene called PICALM was able to produce more than two dozen different circRNAs.
Circular RNAs found in dopaminergic neurons and pyramidal neurons
The researchers then looked for circRNAs that were more common in specific cell types.
They found that 1,526 circRNAs were highly produced by dopaminergic neurons, 3,308 by pyramidal neurons, and 4,860 by non-neuronal cells. CircRNAs associated with dopaminergic or pyramidal neurons also were commonly produced from genes that are known to play a role in synapse function pathways.
“This study provides a unique catalog of circRNAs in two major types of human brain neurons that will be generally useful for decoding [gene] function in neuropsychiatric disease and for advancing the burgeoning field of RNA medicines and diagnostics,” the scientists wrote.
Notably, levels of linear RNA molecules made from these same genes did not significantly distinguish between the three different cell types.
“It was surprising that the circular RNAs rather than the linear RNAs produced from these gene locations defined neuron identity. circRNA diversity provides finely tuned, cell type-specific information that is not explained by the corresponding linear RNAs from the same gene,” said Xianjun Dong, PhD, the study’s first author at Brigham.
In addition, “61% of all synaptic circRNAs were linked to brain disorders,” the researchers wrote.
At least one validated circRNA was produced by 29.4% of 109 genes implicated in Parkinson’s, and by 12.4% of 217 genes linked to Alzheimer’s.
Particularly, levels of the circRNA molecule of the DNAJC6 gene, whose mutations cause juvenile-onset Parkinson’s, were lower in vulnerable dopaminergic neurons at the earliest, prodromal stages of Parkinson’s — even before symptom onset — relative to healthy controls. No such difference was seen for DNAJC6’s linear, protein-coding RNA.
“Naturally occurring circRNAs have the potential to serve as biomarkers for specific brain cells implicated in early, prodromal stages of a disease,” Scherzer said.
Further analyses also suggested an association between the levels of 26 circRNAs in dopaminergic neurons and progressive Lewy body burden, which refers to the toxic buildup of alpha-synuclein protein in the brain that’s thought to play a central role in driving Parkinson’s.
Collectively, these data underscore that circular RNAs have important roles in the biological functioning of brain cells, which may be key in developing treatments for neurological disorders.
“The sheer number and diversity of circRNAs add a new class of components to the growing inventory of … RNAs actively expressed in the human brain disease,” the researchers wrote.
“The fact that circRNAs are predominantly [produced by genes linked to synaptic function] in human dopamine and pyramidal neurons raises the possibility that they encode as yet unknow[n] important functions in … human neuronal networks controlling quintessential human experiences: fine motor movements, motivation, reward, and higher cortical functions,” they added.
Researchers stressed that considerably more work will be necessary to fully comprehend the role of circRNA in the brain.
Still, “circular RNAs cannot easily be broken down, making them a powerful tool as reporters and for delivering therapies,” Scherzer said, adding that “they could be rewritten synthetically and harnessed as future digital RNA medicines.”