In a groundbreaking study from MIT, researchers have uncovered the intricate landscape of RNA editing in neurons, revealing a level of diversity that challenges previous assumptions. The study, published in eLife, examined RNA editing across more than 200 individual cells, focusing on tonic and phasic motor neurons of the fruit fly. This research highlights how neurons, despite originating from the same DNA, develop unique characteristics through varied RNA editing processes.
The research, led by senior author Troy Littleton, the Menicon Professor in MIT’s departments of Biology and Brain and Cognitive Sciences, demonstrates that RNA editing occurs at rates far more varied than the “all-or-nothing” extremes previously assumed. This finding opens new avenues for understanding the role of RNA editing in neural function and its potential applications in genetic therapies.
Unveiling the RNA Editing Landscape
The study’s comprehensive survey of RNA editing identified hundreds of edits in transcripts from a genome of about 15,000 genes. Researchers documented “canonical” edits at 316 sites within 210 genes, facilitated by the enzyme ADAR, which is also present in mammals, including humans. Among these, 175 edits were found in protein-coding regions, with 60 likely to significantly alter amino acids.
Additionally, the study discovered 141 editing sites in non-coding regions, which could influence protein production levels. The presence of numerous “non-canonical” edits, not attributed to ADAR, suggests the involvement of other enzymes, potentially across different species. This discovery could pave the way for broader genetic therapy possibilities.
“We have this ‘alphabet’ now for RNA editing in these neurons,” Littleton says. “We know which genes are edited, allowing us to explore the effects of these edits on neurons.”
Implications for Genetic Therapies
The identification of non-canonical edits is particularly significant for future genetic therapies. Understanding the enzymes responsible for these edits could enhance our ability to repair human genomes where mutations disrupt protein function. Littleton emphasizes the potential for applying this knowledge to address genetic disorders.
Moreover, the study’s focus on fly larvae revealed edits specific to juvenile stages, suggesting developmental significance. By analyzing full gene transcripts of individual neurons, the team identified previously unrecorded editing targets, further expanding the understanding of RNA editing.
Variability and Functionality
One of the study’s key findings is the variability in RNA editing rates among neurons. Some heavily edited RNAs are linked to genes critical for neural circuit communication, such as neurotransmitter release and ion channel regulation. The study identified 27 sites in 18 genes edited more than 90% of the time.
“Some neurons displayed ~100% editing at certain sites, while others showed no editing for the same target,” the team noted. “Such differences likely contribute to the heterogeneous features within the same neuronal population.”
On average, editing occurred at about two-thirds of the sites, with most edits falling between 20% and 70%. This variability suggests that even neurons of the same type can exhibit significant individuality.
Exploring Functional Impacts
The study provides a foundation for exploring the functional impacts of RNA edits. In a 2023 study, Littleton’s lab examined two edits in the complexin gene, which regulates neurotransmitter release. They discovered that different edit combinations produced up to eight protein variants, affecting glutamate release and synaptic currents.
Intriguingly, the study identified a non-canonical edit in the Arc1 gene, crucial for synaptic plasticity. This property allows neurons to adjust synaptic connections in response to activity, a process essential for learning and memory. Notably, Arc1 editing fails in fruit fly models of Alzheimer’s disease, highlighting its potential significance.
The research team, including lead author Andres Crane PhD ’24, Michiko Inouye, and Suresh Jetti, continues to investigate how documented RNA edits affect fly motor neuron function. The study received support from the National Institutes of Health, The Freedom Together Foundation, and The Picower Institute for Learning and Memory.
As the scientific community delves deeper into the complexities of RNA editing, this study sets the stage for future discoveries that could revolutionize our understanding of neural biology and genetic therapies.
