A comprehensive study by scientists at the Brigham and Women’s Hospital, a part of the Mass General Brigham healthcare system, reveals more than 11,000 unique circular RNAs (circRNAs) in brain cells associated with Parkinson’s and Alzheimer’s diseases. These circRNAs could offer significant clues into the molecular underpinnings of these neurological disorders and may have implications for diagnostic markers and RNA-based therapeutics.
Table of Contents
Key Discoveries and Research Methodologies
Researchers, led by Dr. Clemens Scherzer, have been investigating circRNAs in brain cells to deepen our understanding of neurological conditions. Published today in the journal Nature Communications, the study examined 11,000 specific RNA circles in brain cells implicated in Parkinson’s and Alzheimer’s diseases. These circRNAs have often been dismissed as molecular “junk,” but the study argues for their crucial role in human brain cell function and synaptic programming.
The research team employed laser-captured neurons from 190 cryopreserved postmortem human brain samples, which included both neuronal and non-neuronal cells for comparison. They utilized ultra-deep, total RNA sequencing technologies to pinpoint the exact genetic sequences within these circRNAs in two distinct cell types.
A significant 61% of all identified synaptic circRNAs were connected to brain disorders. Of note, the researchers discovered 4,834 cell-type specific circRNAs in dopamine and pyramidal neurons—two critically important types of brain cells. Dopamine neurons govern aspects like movement, mood, and motivation, while pyramidal neurons are vital for memory and language functions.
Assistant professor Dr. Xianjun Dong, the study’s first author, emphasized that circRNAs, not their linear counterparts from the same genes, define the identity of neurons. He suggested that the diversity of circRNAs provides nuanced, cell-specific information not accounted for by corresponding linear RNAs.
Implications and Future Research Avenues
The degenerative processes affecting dopamine and pyramidal neurons are pivotal in the onset of neurological diseases. Researchers uncovered that numerous genes related to Parkinson’s and Alzheimer’s diseases generate circRNAs. Notably, the expression of a circRNA originating from the Parkinson’s-associated gene DNAJC6 showed abnormal levels in susceptible dopamine neurons even before the emergence of clinical symptoms.
Dr. Scherzer suggested that these naturally occurring circRNAs could act as potent biomarkers for early disease stages, as they are notably stable. He further proposed that synthetic versions of these circRNAs could be used in future digital RNA medicines.
The team observed that circRNAs were produced from genes associated with various diseases but in specific cell types. For example, genes linked to addiction produced circRNAs in dopamine neurons, autism-related genes did so in pyramidal neurons, and cancer-associated genes in non-neuronal cells.
The study acknowledges limitations, including an incomplete grasp of the complex mechanisms by which circRNAs influence neuron and synapse identity. Further studies are needed to explore how circRNAs are formed and operate, and to identify additional genetic factors that regulate their behavior.
The current findings represent the most exhaustive analysis of circRNAs in human brain cells to date and open up avenues for leveraging these molecules in diagnostics and treatment modalities for neurological disorders.
Additional Information
Funding for this research was partly provided by the American Parkinson Disease Association, the National Institutes of Health (NIH), and the U.S. Department of Defense, along with supplementary contributions from the ASAP Foundation.
Disclosures: Dr. Clemens Scherzer has served as a consultant or scientific advisor for companies such as Sanofi, Berg Health, Pfizer, and Biogen, and has received grants from multiple organizations including the NIH and the U.S. Department of Defense. Dr. Xianjun Dong has also received funding from NIH, the American Parkinson Disease Association, and the ASAP Foundation.
Frequently Asked Questions (FAQs) about circRNAs in neurological diseases
What are circRNAs and why are they important in the study of neurological diseases?
Circular RNAs (circRNAs) are a type of RNA molecule that, unlike linear RNAs, form a covalently closed continuous loop. They have long been considered as ‘junk’ in cellular biology. However, the study led by scientists at the Brigham and Women’s Hospital reveals that these circRNAs play a crucial role in brain cell function and synaptic programming, especially in cells associated with Parkinson’s and Alzheimer’s diseases.
Who conducted this research and where was it published?
The research was conducted by a team of scientists led by Dr. Clemens Scherzer at the Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system. The findings were published in the journal Nature Communications on September 18.
What methodologies were used in this research?
The team employed laser-captured neurons from 190 cryopreserved postmortem human brain samples for the study. They utilized ultra-deep, total RNA sequencing technologies to precisely identify the genetic sequences within the circRNAs in two distinct cell types: neuronal and non-neuronal.
What were the key findings of the research?
The research identified over 11,000 unique circRNAs in brain cells associated with Parkinson’s and Alzheimer’s diseases. A significant 61% of all synaptic circRNAs were connected to brain disorders. Importantly, the expression of a circRNA originating from a Parkinson’s-associated gene showed abnormal levels even before the onset of symptoms.
What are the potential applications or implications of these findings?
The findings suggest that circRNAs could serve as stable biomarkers for early disease detection. Additionally, synthetic versions of these naturally occurring circRNAs could be developed for use in future RNA-based therapeutic treatments for neurological disorders.
What are the limitations of the study?
The study acknowledges that there is still an incomplete understanding of how these circRNAs influence neuron and synapse identity. Future research is needed to explore how circRNAs are formed and operate, and to identify additional genetic factors that influence their behavior.
Who funded the research?
The study was partly funded by the American Parkinson Disease Association, the National Institutes of Health (NIH), and the U.S. Department of Defense, with additional contributions from the ASAP Foundation.
Are there any disclosures related to this research?
Dr. Clemens Scherzer has served as a consultant or scientific advisor for companies such as Sanofi, Berg Health, Pfizer, and Biogen, and has received grants from multiple organizations. Dr. Xianjun Dong has also received funding from NIH, the American Parkinson Disease Association, and the ASAP Foundation.
More about circRNAs in neurological diseases
- Nature Communications Journal Article
- Brigham and Women’s Hospital Research Department
- Mass General Brigham Healthcare System
- American Parkinson Disease Association Funding Page
- National Institutes of Health (NIH) Research Grants
- U.S. Department of Defense Research Funding
5 comments
Wow, this is groundbreaking stuff! Always thought RNA was kinda simple but seems like its more complex than we ever imagined.
this kinda research is why I’m studying neurology! There’s so much we don’t know about the brain yet. Also, kudos to the team for using such advanced methodologies.
Interesting but let’s not get ahead of ourselves. Lots more research needed before we start talking about RNA-based treatments and cures.
fascinating read. Who woulda thought that junk RNA circles would end up having a big role in such serious diseases. Makes ya think.
Absolutely intriguing. I’ve been following Dr. Scherzer’s work for years, and this is a huge step forward. Eager to see what comes next.