KAIST announced on the 14th that a research team led by Professor Yoon Ki-joon of the Department of Biological Sciences (in photo) has identified the principle of so-called “RNA delivery service” by which ribonucleic acid (RNA), the genetic material inside neurons that make up the brain, is transported to where it is needed. The team confirmed that a small chemical modification attached to RNA, N6-methyladenosine (m6A) – comparable to a shipping label on a parcel – serves as the delivery address. With this new criterion of “accurate delivery” added to existing brain disease research, which has focused only on whether RNA is “properly formed,” the findings are expected to open a breakthrough in therapeutic development.

Neurons in the brain are elongated like tree branches, making RNA transport particularly challenging. In many cases, RNA produced in the cell body (nucleus) is actually used at the far-removed axon terminal. An axon is a thin projection that sends electrical signals to other neurons; only when it grows correctly and forms proper connections can the brain develop and function normally.

While previous brain disease research has focused on whether RNA is “properly formed,” this study adds a new standard: whether RNA “reaches the correct destination.” Even well-formed RNA can lead to brain disease if it fails to arrive at the axon terminal. In fact, prior studies have shown that abnormal regulation of m6A is associated with Alzheimer’s disease.

The research team first analyzed mice in which the enzyme responsible for attaching m6A to RNA was inactivated, effectively preventing the attachment of shipping labels. As a result, neuronal projections failed to grow properly. The team then created a high-resolution map, at the single-nucleotide (base) level, showing exactly which RNAs in the mouse brain carry m6A and at which positions. They also identified the roles of specific proteins and the transport system. When the protein YTHDF2 reads the m6A shipping label, it forms a complex with the proteins FMRP and KIF5C to carry RNA all the way to the axon terminal. If YTHDF2 is the address reader, the other two function as delivery vehicles. The study was published in the July 30 edition of the international journal Nature Communications.

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