Grant: Project Grant

The translation of messenger RNAs (mRNAs) to synthesize proteins is a fundamental process in all cells. Protein synthesis is performed by ribosomes-complex molecular machines containing over 85 components. For protein synthesis to be effective, it must occur locally, precisely where the proteins are needed. As most cells are 10-20 µm in size, ribosomes can easily synthesize proteins where they are needed. However, neurons have a unique shape characterized by long extensions called dendrites and axons, which can be up to 1 m long. Our previous research showed that neurons use a unique cellular process to ensure the timely transport of mRNAs and ribosomes from the neuron's main body (the soma, where mRNAs and ribosomes are synthesized) to these distal sites. We found that neuronal ribosomes initiate protein synthesis in the soma, stall the process, and then get packaged into structures called neuronal RNA granules, which are transported to the dendrites and axons, where protein synthesis resumes. How this process works remains unknown; however, it is clear that neuronal RNA granules differ from both actively translating polysomes and other types of RNA granules that are found in other cells in the body. In this Project Grant, we will use cutting-edge structural, cell biology, and machine learning techniques to uncover the unique characteristics of neuronal ribosomes that enable this specialized transport mechanism (Aim 1), identify the mRNA sequences that trigger stalling (Aim 2), and analyze the higher-order organization of ribosome clusters in neuronal RNA granules (Aim 3). This will help reveal the roles of specific proteins within these granules and explain how the ribosomes evade recycling. Many neurodevelopmental disorders, such as Fragile X syndrome, arise when this transport mechanism is disrupted. Therefore, understanding these mechanisms will enable the development of novel therapies that improve the outcomes of affected individuals.