Despite our understanding of the role of the survival motor neuron protein (SMN) in cytoplasmic small ribonucleoproteins (snRNP) assembly, it is unclear how loss of this protein causes motor neuron degeneration in Spinal Muscular Atrophy (SMA). It could be explained by defects in functions that are specific to tissues most affected in SMA. In neurons, SMN localizes to neuronal RNA granules, RNA-containing foci in axons. They regulate many aspects of mRNA fate which include transport along neurites, mRNA stability, and mRNA translation. Most recently, our work provided evidence for SMN’s role in mRNA translation. Specifically, we demonstrated that SMN associates with polyribosomes and may repress translation of specific mRNA targets. Our group demonstrated that SMA-causing mutations within the Tudor domain of SMN completely abolished this activity. This indicates the potential significance of this novel SMN function in the SMA pathology. To further investigate SMN’s function in regulating translation, our group performed a proteomic screen on polysome-containing sucrose gradient fractions. We identified and validated novel interacting partners for SMN that may act as co-factors to regulate translation. DDX5 (an RNA helicase) is an unexpected novel interacting partner as it is known for its role in micro-RNA processing. Moreover, we observe that FMRP, a recognized protein in translational complexes, is required for the presence of SMN and DDX5 in polysomal fractions. With these latest findings, we updated our model of the molecular mechanism by which SMN regulates translation. This work provides more insights on how SMN regulates translation, a newly uncovered role for SMN in motor neurons. Identification of the molecular targets that are misregulated due to loss of this function may reveal new information on the pathogenesis of SMA.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/37057 |
| Date | January 2017 |
| Creators | Mostefai, Fatima |
| Contributors | Côté, Jocelyn |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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