Axonal mRNA Transport

Description of Axonal mRNA Transport

Neurons refer to highly polarized cells, it is well-known that axons and dendrites constitute most of the volume and surface area of a neuron. Axons provide remote connections between neurons to achieve communication between the brain, spinal cord, and peripheral nerves. Axons extend very long distances from neuronal cell bodies, and local mRNA translation has been used to respond to a variety of extracellular stimuli and physiological states. In this case, the mechanisms have been developed for local proteins to synthesize to perform specialized functions. In recent years, accumulating evidence supports the importance of mRNA localization as well as the synthesis of localized protein in the development, maintenance, and function of neurons.

Fig.1 Ribonucleoprotein (RNP)-coupled transport of mRNAs into axons. (Dalla 2020)

Mechanism for Axonal mRNA Transport Regulation

Just like proteins and organelles, mRNA can be transported into axons by molecular motors. And mRNA is transported in protein complexes as "RNA transport particles", that is, ribonucleoprotein complex (RNP). Analyses of RNP showed that the RNPs are from dendrites, axons, and soma. Several RNA-binding proteins (RBPs) have been found in axons, but the number is vastly smaller than the thousands of mRNAs. In this case, these RBPs may interact with many different mRNAs and a single axon mRNA can also interact with several different RBPs. For example, the binding of some axonal RBPs, such as nucleolin, FUS/TLS, YB-1, CD44, TDP-43, and FMRP, to individual mRNAs has been characterized. There are also some axonal RBPs, including TRF2-S, ZBP-1, and HuD, which have been proved to interact with multiple mRNAs.

Axonal mRNA Transport with Neurological Disease

The recent studies indicated that the disruption of multiple steps in mRNA processing, transport, local synthesis, and retrograde signaling would result in a series of neurodevelopmental and neurodegenerative diseases. And altered axonal RNA transport can impact axon growth, function, and survival. There are multiple RBPs have been detected in axons linked to neurological diseases. For example, the mutation of TDP-43 and FUS/TLS has been detected in amyotrophic lateral sclerosis (ALS), the deficiency of SMN leads to spinal muscular atrophy (SMA), and loss of SFPQ from axons contributes to peripheral neuropathy. A better understanding of axonal mRNA transport may lead to potential therapeutic strategies.

Fig.2 Multiple sites along the axonal protein synthesis continuum have been implicated in neurological disease. (Costa 2018)

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References

1. Dalla, Costa.; et al. The functional organization of axonal mRNA transport and translation. Nature Reviews Neuroscience. 2020: 1-15.
2. Costa, C.; Willis, D. To the end of the line: Axonal mRNA transport and local translation in health and neurodegenerative disease. Developmental neurobiology. 2018, 78(3): 209-220.