- Chemical tag m6A acts as a 'delivery label,' guiding RNA to the far ends of neurons

- Study reveals new transport function of YTHDF2, previously known only as an RNA-degrading protein

- Findings expected to shed light on RNA delivery errors behind neurodevelopmental and degenerative brain diseases

From left, KAIST Department of Biological Sciences students Koo Bon-sang, Hwang Hee-sun and Park Min-young, and Professor Yoon Ki-jun, who led the research. [KAIST]
From left, KAIST Department of Biological Sciences students Koo Bon-sang, Hwang Hee-sun and Park Min-young, and Professor Yoon Ki-jun, who led the research. [KAIST]

Scientists have uncovered the workings of a previously unknown RNA delivery system in neurons — one that selects specific RNA molecules and transports them precisely to the far ends of brain cells.

KAIST announced Monday that a research team led by Professor Yoon Ki-jun of the Department of Biological Sciences has identified a key mechanism by which m6A, a chemical tag attached to RNA, plays a central role in carrying certain RNA molecules all the way to the tip of the axon — the long, slender channel neurons use to transmit signals.

Unlike most cells, neurons have a uniquely elongated structure. The axon serves as the conduit through which signals are sent to other neurons. RNA produced at the cell's center may be needed at a distant axon terminal, making the selective transport of the right RNA to the right destination critical for normal neuronal growth and function.

The research team found that m6A acts as a kind of "delivery label" in this process.

When the team analyzed mice engineered so that the methylation enzyme responsible for attaching m6A to RNA could not function properly, neurite growth — the elongation of projections from neurons — was significantly impaired.

The team then used a technology called m6A-SAC-seq to build a high-resolution map of where m6A modifications appear on RNA in mouse brains, down to the level of individual nucleotides. The analysis confirmed that m6A tags are also present on specific RNA molecules required for axon growth.

The key to the system lies in the protein that reads this "delivery label."

The team found that the protein YTHDF2 recognizes m6A-tagged RNA and works together with FMRP and KIF5C to move that RNA to the ends of neurons. In this analogy, m6A is the shipping label on a parcel, YTHDF2 is the reader that identifies it, and FMRP and KIF5C form the transport system that carries it to its destination.

A diagram illustrating the molecular mechanism by which m6A RNA methylation promotes RNA transport and axonal connectivity within neurons. [KAIST]
A diagram illustrating the molecular mechanism by which m6A RNA methylation promotes RNA transport and axonal connectivity within neurons. [KAIST]

Particularly notable is the newly discovered role of YTHDF2. The protein had previously been known primarily as a promoter of RNA degradation — breaking down unnecessary RNA. This study reveals that it also transports needed RNA to its destination, a function not previously attributed to it. Research showed that a complex formed by YTHDF2 and FMRP links m6A-tagged RNA to microtubules and motor proteins, enabling it to travel to neurite terminals.

The team is now building similar m6A maps in human neurons, patient-derived induced pluripotent stem cells and brain organoids, with plans to compare how RNA regulation and transport differ between normal neurodevelopment and disease states.

The next goal is to confirm whether the RNA transport system identified in this study operates the same way in human neurons, and to determine what changes occur in neurodevelopmental and degenerative brain diseases. If the findings can be developed into a technology that selectively controls the transport of specific RNA molecules, they could lead to new treatment strategies for brain diseases.

"This will serve as a foundation for understanding why RNA fails to reach where it is needed in brain diseases, and for exploring new treatment possibilities," Yoon said.

The findings were published in Nature Communications.


nbgkoo@heraldcorp.com