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Elucidating the mechanisms facilitating RNA capture and translation at dendritic spines


   College of Medicine and Veterinary Medicine

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  Dr Paul Donlin-Asp  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

Applications are invited for one 3.5 year full-time fully funded PhD studentship in the lab of Dr Paul Donlin-Asp (https://www.donlin-asp-lab.com/) within the Simons Initiative for the Developing Brain at the University of Edinburgh. SIDB (www.sidb.org.uk) is a philanthropic Centre funded by the Simons Foundation Autism Research Initiative (www.sfari.org).

Title: Elucidating the mechanisms facilitating RNA capture and translation at dendritic spines

Background: Given that more than 75% of a neuron’s volume resides within its distal processes, a fundamental logistic challenge for the neuron is how it can rapidly and efficiently modulate its proteome to facilitate learning. In part, neurons overcome these distance constraints by localizing mRNAs to synapses and locally producing proteins. RNAs are believed to be transported in a protein synthesis quiescent state- only engaged in protein synthesis near synapses. They exhibit dynamic and bidirectional scanning behaviour, believed to facilitate mRNA being translated at discrete locations. Previous work suggests RNAs are recruited to spines through a two-step mechanism: a non-specific capture of mRNA by any activated synapse, and a subsequent decoding step determining if it is translated.

Aims and training:

  1. Using novel genetically encodable RNA sensors, track the dynamic properties of several endogenous mRNAs in live neurons during synaptic plasticity.
  2. Using metabolic labelling and proximity ligation (Puro-PLA) assess the context specific local translation of these target mRNAs during synaptic plasticity.
  3. Using pulldowns and proteomic analysis- assess the molecular changes in the factors associated with targeted mRNA to understand how capture and translation is regulated.

Expertise is available in all the necessary techniques, and we have access to excellent super resolution microscopy facilities through ESRIC.

Rationale & hypothesis: While >4800 mRNAs can localize in dendrites and axons, the copy number of individual mRNAs are sparse- with single mRNAs existing at densities below one mRNA per micron of dendrite. Furthermore, an individual mRNA molecule is massive compared to proteins, meaning it’s unlikely an individual spine could host more than two or three at any given time. These constraints highlight the advantages of a two-step capture and decode mechanism at the synapse. With such low densities of specific mRNAs- we hypothesize an activated spine will grab any mRNAs passing nearby. This mechanism of capture, decoding, and translation has been seen only for a few mRNAs. With novel genetically encodable RNA tracking systems we’ll be able to explore the dynamics and capture of any endogenous RNA of interest.

Eligibility: Applicants should have a good (2:1 or higher) undergraduate degree in a relevant subject (including, not limited to, neuroscience, biomedical sciences, molecular biology, genetics, or computational biology).

Candidates should also meet the entry requirements for admission to postgraduate programmes at the University of Edinburgh.

Funding: This is a SIDB funded award. It will provide an annual stipend for 3.5 years of £20,000 per annum, plus tuition fees (including international).

How to Apply: Please email Natacia Hambakis Hatch ([Email Address Removed]) to request an application form. Once you have completed the form you should return it direct, along with your references, to Natacia Hambakis Hatch at the same email address. Please contact Paul Donlin-Asp as well ([Email Address Removed]) to discuss questions and the nature of your interest in the project. In the application form you should indicate why you are interested in the project and why you would be a good fit for the project.

Deadline: The deadline for applications is 16th January 2023.

Start time: The start time for the studentship is September 2023.


References

Donlin-Asp PG, Polisseni C, Klimek R, Heckel A, Schuman EM (2021) Diifferential regulation of local mRNA dynamics and translation following long-term potentiaion and depression.
Hafner AS*, Donlin-Asp PG*, Leitch B, Herzog E, Schuman EM. (2019) Local protein synthesis is a ubiquitous feature of neuronal pre- and postsynaptic compartments. Science.*equal contribution

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