Nature Communications: Scientists Identify Unique Circular RNAs in Parkinson's Disease

Researchers from Harvard Medical School have made a significant discovery related to over 11,000 different circular RNAs, which appear to have characteristics associated with Parkinson's disease and Alzheimer's disease in brain cells. The study was published in the journal Nature Communications titled "Circular RNAs in the human brain are tailored to neuron identity and neuropsychiatric disease.

Circular RNAs have long been considered to be mere byproducts, but we now understand that they play a crucial role in the programming of human brain cells and synapses. The authors have found that brain cells produce a large number of circular RNAs, including those related to brain cells associated with Parkinson's disease and Alzheimer's disease. Subsequently, the researchers used laser capture to analyze neurons in brain samples from 190 deceased individuals, including non-neuronal cells for comparison. They employed ultra-deep whole RNA sequencing techniques to investigate the exact sequences of genetic codes in circular RNAs in these two cell types. The researchers found that 61% of all synaptic circular RNAs were associated with brain diseases. Notably, they also discovered 4,834 cell type-specific circular RNAs in high-functioning brain cells such as dopamine and pyramidal neurons. Dopamine neurons control movement, emotions, and motivation, while pyramidal neurons play a vital role in memory and language in the body.

These circular RNAs are generated from specific gene loci, rather than linear RNAs, that determine the identity of neurons. The diversity of circRNAs provides fine-tuned, cell-type-specific information that linear RNAs from the same gene cannot explain. The degeneration of these dopamine and pyramidal neurons plays a crucial role in the development of neurological diseases. When investigating this connection, researchers found an astonishing abundance of circular RNAs produced by Parkinson's disease genes, like DNAJC6, in susceptible dopamine neurons, with their expression decreasing even before patients displayed symptoms. Naturally occurring circular RNAs hold promise as biomarkers for specific brain cells in early disease and precursor stages. They are not easily degraded, making them a powerful tool for reporting and therapeutic interventions in the future, as they can be synthesized and rewritten as digital RNA drugs.

Fig.2 CircRNAs are linked to neuropsychiatric disease.

The researchers also discovered that genes associated with different diseases can produce circular RNAs in specific cell types. For example, addiction-related genes can produce circular RNAs in dopamine neurons, while autism-related genes produce circular RNAs in pyramidal neurons, and cancer-related genes produce circular RNAs in non-neuronal cells. The current limitations of the research include an incomplete understanding of how this complex RNA machinery dictates neuron and synapse properties. In future studies, researchers hope to investigate how these circular RNAs function and explore other genetic regulatory factors behind their actions. Nevertheless, the current research provides the most comprehensive analysis of circular RNAs in human brain cells to date, suggesting their potential utility in RNA diagnostics and aiding in the treatment of human neurological disorders.

The discovery of circular RNAs has changed our understanding of the molecular mechanisms behind human neurodegenerative diseases. Circular RNAs are more durable than linear RNAs and hold promise as RNA therapies and RNA biomarkers. In summary, the results of this study indicate that circular RNAs in the human brain may be tailored according to neuron identity and may link circular RNA regulation to synaptic specialization in human neuropsychiatric diseases.