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Mechanisms determining the dynamic localisation of ribosomes in neurons


Project Description

Neurons form complex extended cellular structures. For example, motoneurons, have cell bodies in the spinal cord whilst extending axons down to the muscles of hands and feet. It is now established that axons use local translation, allowing rapid alteration of the proteome in response to environmental changes during development or injury. However, the local translation machinery must itself reach the distal axon using axonal transport mechanisms. For a metre long axon this can be many days or even weeks and defects in transport are observed in many neurodegenerative conditions, including Alzheimer’s, Parkinson’s, Huntington’s and ALS. There can be no local translation without ribosomes; the goal of this project is to understand for the first time how ribosomes are localised to axons. You will be trained in advanced, real-time imaging and analysis, cell biological (primary and stem cell derived neuronal culture) and biochemical approaches, including state of the art next generation RNA-Protein crosslinking strategies (e.g. CLIP and CRAC). There is also potential to develop super-resolution (PALM/STORM) and CRISPR/Cas9 genome editing approaches to support the project. This research will provide fundamental insights into axonal transport, with translational outcomes for neurodegenerative diseases.

Funding Notes

The UPGRC Scholarships for Medicine, Dentistry & Health are 3.5 years in duration and cover fees and stipend at Home/EU level. Overseas students may apply but will need to fund the fee differential between Home and Overseas rate from another source.

Please note the deadline for submitting applications is 5pm on the 23rd January.

References

Heuer, André, Emma Thomson, Christian Schmidt, Otto Berninghausen, Thomas Becker, Ed Hurt, and Roland Beckmann. 2017. “Cryo-EM Structure of a Late Pre-40S Ribosomal Subunit from Saccharomyces Cerevisiae.” eLife 6 (November). https://doi.org/10.7554/eLife.30189.

Khalil, Bilal, Dmytro Morderer, Phillip L. Price, Feilin Liu, and Wilfried Rossoll. 2018. “mRNP Assembly, Axonal Transport, and Local Translation in Neurodegenerative Diseases.” Brain Research 1693 (Pt A): 75–91.

Leterrier, Christophe. 2016. “The Axon Initial Segment, 50Years Later: A Nexus for Neuronal Organization and Function.” Current Topics in Membranes 77: 185–233.

Maday, Sandra, Alison E. Twelvetrees, Armen J. Moughamian, and Erika L. F. Holzbaur. 2014. “Axonal Transport: Cargo-Specific Mechanisms of Motility and Regulation.” Neuron 84 (2): 292–309.

Sarkar, Anshuk, Matthias Thoms, Clara Barrio-Garcia, Emma Thomson, Dirk Flemming, Roland Beckmann, and Ed Hurt. 2017. “Preribosomes Escaping from the Nucleus Are Caught during Translation by Cytoplasmic Quality Control.” Nature Structural & Molecular Biology 24 (October): 1107.

Scarnati, Matthew S., Rahul Kataria, Mohana Biswas, and Kenneth G. Paradiso. 2018. “Active Presynaptic Ribosomes in the Mammalian Brain, and Altered Transmitter Release after Protein Synthesis Inhibition.” eLife 7 (October). https://doi.org/10.7554/eLife.36697.

Shigeoka, Toshiaki, Hosung Jung, Jane Jung, Benita Turner-Bridger, Jiyeon Ohk, Julie Qiaojin Lin, Paul S. Amieux, and Christine E. Holt. 2016. “Dynamic Axonal Translation in Developing and Mature Visual Circuits.” Cell 166 (1): 181–92.

Thoms, Matthias, Emma Thomson, Jochen Baßler, Marén Gnädig, Sabine Griesel, and Ed Hurt. 2015. “The Exosome Is Recruited to RNA Substrates through Specific Adaptor Proteins.” Cell 162 (5): 1029–38.

Twelvetrees, Alison E., Stefano Pernigo, Anneri Sanger, Pedro Guedes-Dias, Giampietro Schiavo, Roberto A. Steiner, Mark P. Dodding, and Erika L. F. Holzbaur. 2016. “The Dynamic Localization of Cytoplasmic Dynein in Neurons Is Driven by Kinesin-1.” Neuron 90 (5): 1000–1015.

Virlogeux, Amandine, Eve Moutaux, Wilhelm Christaller, Aurélie Genoux, Julie Bruyère, Elodie Fino, Benoit Charlot, Maxime Cazorla, and Frédéric Saudou. 2018. “Reconstituting Corticostriatal Network on-a-Chip Reveals the Contribution of the Presynaptic Compartment to Huntington’s Disease.” Cell Reports 22 (1): 110–22.

Zhang, Jun, Alison E. Twelvetrees, Jacob E. Lazarus, Kiev R. Blasier, Xuanli Yao, Nirja A. Inamdar, Erika L. F. Holzbaur, K. Kevin Pfister, and Xin Xiang. 2013. “Establishing a Novel Knock-in Mouse Line for Studying Neuronal Cytoplasmic Dynein under Normal and Pathologic Conditions.” Cytoskeleton 70 (4): 215–27.

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