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Human Brain Circular RNAs Linked to Neuron Type, Neuropsychiatric Conditions

NEW YORK – A team from the US and China has characterized circular RNAs (circRNAs) in different brain cell types, uncovering cell type-specific circRNAs and potential markers for conditions such as Parkinson’s or Alzheimer’s disease.

"We are on a mission to map the entire RNA code — including all noncoding and coding RNAs — of human brain cells and to reveal how glitches cause Parkinson’s and other neuropsychiatric diseases," senior and corresponding author Clemens Scherzer, director of Brigham and Women’s Hospital’s APDA Center for Advanced Parkinson Research, said in an email.

He noted that most prior studies of these conditions, and the brain in general, have focused on the small subset of genome sequences that code for known proteins, despite expression of RNA in brain cells that vastly exceeds those needed to produce these proteins.

As they reported in Nature Communications on Monday, Scherzer and his colleagues turned to ultra-deep RNA sequencing to profile 212 neuron samples obtained by laser capture microdissection from the motor cortex, temporal cortex, and substantia nigra regions of 190 frozen, post-mortem human brains collected for the BRAINcode project. These included brains from donors with Parkinson’s or Alzheimer’s disease, as well as from unaffected controls.

They also profiled RNAs in several non-brain samples and obtained RNA-seq profiles from bulk brain samples.

The team’s analyses made it possible to pick up RNA transcripts present at low levels in dopamine-producing neurons that are lost in Parkinson’s disease, as well as in pyramidal neurons that tend to be affected in individuals with Alzheimer’s disease.

"Compared to most brain RNA-seq studies, our method provides ultra-deep sequencing depth and reveals low-abundance transcripts," the authors explained, noting that the laser-capture RNA-seq strategy "captures total RNAs without limitation of [polyadenylated messenger RNAs], allowing us to detect non-polyadenylated RNAs such as circRNAs."

After quality control steps, the investigators were left with data for 190 brain and seven non-brain samples, highlighting more than 111,400 circRNAs found by sequencing of microdissected samples and nearly 39,900 circRNAs identified by bulk RNA-seq profiling.

At the intersection of these methods, meanwhile, the team saw 11,039 neuronal circRNAs that were found by both sequencing strategies — a set that included 1,526 circRNAs that appeared specific to dopamine-producing neurons and 3,308 pyramidal neuron-specific circRNAs.

"The latest results add 11,039 circRNAs to this RNA encyclopedia of human brain cells, on top of 71,022 putative enhancer RNAs, and tens of thousands of long noncoding and coding RNAs," Scherzer said.

When the researchers took a closer look at these cell type-specific sequences, they found that the circRNAs tended to originate from genes involved in synapse-related pathways. Conversely, their results suggested that nearly one-third of Parkinson’s disease-associated genes appeared to produce circRNAs, as did some 12 percent of genes implicated in Alzheimer’s disease.

"The fact that circRNAs are predominantly expressed from synapse loci in human dopamine and pyramidal neurons raises the possibility that they encode as yet unknow[n] … synaptic functions of the human neuronal networks controlling quintessential human experiences: fine motor movements, motivation, reward, and higher cortical functions," the authors explained, noting that the work "expands on a postulated role for circRNAs in synaptosomes and synaptic plasticity in animals."

At least one of the Parkinson’s disease-related circRNAs, dubbed circDNAJC6, appeared to be altered early on during the process of disease development, the team explained, pointing to the possibility of establishing biomarkers based on circRNA molecules, which remain stable for longer stretches of time than linear RNA molecules.

Scherzer suggested that the next step in biomarker development would involve a search for disease-related circRNAs that originate in the brain but can be measured in samples that can be collected in the clinic, such as cerebrospinal fluid.

He noted that the identification of circRNAs with disease-related shifts in expression or regulation may provide an avenue for treating some conditions. If such molecules have a role in disease features, for example, it may be possible to chemically synthesize therapeutic molecules to replace or repair altered circRNAs.

"[T]his 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," he and his coauthors wrote.

More broadly, the investigators noted that circRNAs produced by genes associated with other conditions, including addiction, autism spectrum disorder, bipolar disease, or cancer, seem to turn up in related brain or non-brain cell types.

On the other hand, circRNAs stemming from atrial fibrillation-linked genes turned up in pyramidal neurons, the authors reported, "pointing to a potential role of synaptic plasticity in cardiac innervation."

Based on their results so far, they suggested, "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."