College of Medicine Professor Hosung Jung and his team have uncovered the function of local mRNA translation in the formation and maintenance of neural circuits. Neurons make long-distance connections via their axons, which need a number of different proteins. The problem is that DNA, the blueprint to make proteins, resides in the neuronal cell body, which is often remote from the axon terminal. How proteins needed at the axon terminal are supplied in a timely manner has remained a puzzle. One idea, which was confirmed in this research, was that the neuron transcribes messenger RNAs (mRNAs) from its DNA in the cell body, transport them in a translationally repressed form to the axon terminal, and synthetize specific proteins when and where they are needed by local mRNA translation.
To test this hypothesis, they developed a new technique called axon-TRAP (translating ribosome affinity purification), which allows isolation of mRNAs being translated into proteins at the axon terminal in mouse in vivo. Using this technique, they discovered that specific mRNAs are locally translated into proteins necessary for making (or pruning) connections (or synapses) as the neural circuity is being built. An unexpected finding was that axonal local mRNA translation continues in the mature nervous system, where it is used to make proteins necessary for axon survival. The research could have important applications for the understanding of neurodegenerative disorders, which often result from failure to maintain axonal integrity. According to Professor Jung: “Although a strong genetic link has been found between the mutations in the RNA-binding proteins (RBPs) and neurodegenerative disorders like amyotrophic lateral sclerosis (ALS) in human genetics, mechanistic details to explain this link was lacking. Because RBPs regulate mRNA splicing, transport and translation, this research enables us to view the cause of neurodegenerative diseases from a new perspective: dysfunctional RBPs prevent local translation of axon survival proteins.”
Joining Professor Jung were two of his graduate students, Jane Jung and Jiyeon Ohk, and Professor Christine Holt’s research team of University of Cambridge. Their findings were published June 30 in Cell under the title “Dynamic Axonal Translation in Developing and Mature Visual Circuits.”