In a new editorial, researcher Hana Hall discusses the role of R-loops in neuronal aging and neurodegeneration.
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R-loops are structures that form when the nascent RNA hybridizes with the template DNA strand, displacing the non-template strand. In other words, R-loops are like temporary tangles in our DNA where a new RNA molecule forms by copying one of the DNA strands and pushes aside the other DNA strand. Nascent RNA refers to the newly synthesized RNA molecule that is produced during the process of transcription. In addition to transcription, R-loops are involved in various biological processes, such as splicing, DNA repair and chromatin remodeling. However, when R-loop homeostasis is disrupted, they can also cause transcriptional impairment, genome instability and cellular dysfunction.
“R-loops have been shown and studied in a wide range of organisms and while they have important regulatory roles, persistent R-loops can be detrimental to cell function and survival, having been closely linked to both gene expression dysregulation and increased genome instability.”
In a new editorial paper, researcher Hana Hall from the Purdue Institute for Integrative Neuroscience at Purdue University discusses the role of R-loops in neuronal aging and neurodegeneration. On September 13, 2023, her editorial was published in Aging’s Volume 15, Issue 17, and entitled, “R-loops in neuronal aging.” Hall summarizes her recent study and the current knowledge on how R-loop levels change during aging, how they affect gene expression and neuronal function, and how they are regulated by different factors.
“In our recent study, we demonstrated that R-loops accumulate in fly PR [photoreceptor] neurons by middle age and significantly increase into late-life stages [5].”
The Editorial
According to Hall, R-loop levels increase with age in different organisms and tissues, including neurons. This could be due to several reasons, such as reduced expression or activity of R-loop resolving enzymes (e.g., Top3β, RNase H1), increased transcriptional activity or stress, or impaired DNA repair mechanisms. Hall also highlighted that R-loop accumulation is associated with decreased expression of long and highly expressed genes, which are enriched for neuronal functions. This could lead to impaired neuronal activity and communication, as well as increased vulnerability to neurodegenerative diseases.
“Our study provides first evidence of R-loop accumulation in aging neurons and a contributing role in loss of neuronal function during aging.”
Hall further discussed how R-loop homeostasis is modulated by various factors, such as chromatin structure, epigenetic modifications, RNA-binding proteins, and non-coding RNAs. She also mentioned some potential therapeutic strategies to restore R-loop balance in aging neurons, such as overexpressing or delivering R-loop resolving enzymes, modulating chromatin accessibility or targeting specific R-loop forming genes.
Conclusions
Hall concluded that R-loops are important players in neuronal aging and neurodegeneration, and that more studies are needed to understand their molecular mechanisms and functional consequences. She also suggested that R-loop mapping could be used as a biomarker to monitor neuronal health and disease progression. This editorial provides a comprehensive overview of the current knowledge of R-loops in neuronal aging, and highlights the challenges and opportunities for future research.
“Undoubtedly, R-loops are at the crossroads of several hallmarks of aging, namely transcriptional stress, genome instability, and chronic immune response. Targeting R-loop levels thus may help restore these pathways to a normal/healthy state and slow down or prevent the onset of age-dependent neurodegenerative diseases.”
Click here to read the full editorial published in Aging.
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