Don't miss our weekly PhD newsletter | Sign up now Don't miss our weekly PhD newsletter | Sign up now

  Investigating the molecular mechanisms underlying dysregulated synaptic plasticity in neurodevelopmental disorders


   Simons Initiative for the Developing Brain

This project is no longer listed on FindAPhD.com and may not be available.

Click here to search FindAPhD.com for PhD studentship opportunities
  Dr Susana Louros  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 Susana Louros 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: Investigating the molecular mechanisms underlying dysregulated synaptic plasticity in neurodevelopmental disorders

Background: Previous work indicates that protein synthesis and degradation are necessary for the remodelling of synapses. These two processes govern cellular protein turnover, are tightly regulated, and are modulated by neuronal activity in time and space. We have recently shown that protein degradation is upregulated in Fmr1 KO mice, downstream of the increased protein synthesis rates and that restoring protein degradation corrects pathological hallmarks in the Fmr1 KO mouse (Louros, Seo et al, 2023). Furthermore, we found that several genes involved in ubiquitination are overexpressed in the Fmr1 KO brain (Louros, Seo et al, 2023) and we can correct the excessive protein synthesis when reducing ubiquitination rates. This suggests that ubiquitination is modulating the increase in protein synthesis in Fmr1 KO mice, but how this underlying defect in synaptic plasticity in the hippocampus remains unknown. Importantly, this raises the possibility that targeting aberrantly ubiquitinated proteins may provide targeted therapeutic approaches for neurodevelopmental disorders, such as Fragile X syndrome. In this project, we will test the hypothesis that ubiquitination dysregulation contributes to learning and memory deficits in the Fmr1 KO mouse and that this can be restored using molecular glues, such as PROTACs.

Aims:

To test this hypothesis, we will combine imaging with cell-type specific proteomics and functional assays in Fmr1 mutant models, to address 3 main aims:

  • Aim 1: Determine how ubiquitination is dynamically regulated at synapses in Fmr1 KO mice/rats during synaptic plasticity using proteasome and ubiquitination reporters and proteomics
  • Aim 2: Characterise protein turnover dysfunction in excitatory neurons from Fmr1-/y mice/rats, using cell-type specific proteomics in vivo
  • Aim 3: Develop molecular glue strategies (PROTACs) to correct excessive mGluR-LTD and learning deficits of Fmr1 KO mice/rats

Training outcomes:

By the end of the project, the PhD student will be trained to perform PCR, Western blot, cloning, immunoprecipitation, mass-spectrometry, immunofluorescence, neuronal dissociated and organotypic cultures as well as proteomics approaches to quantify protein turnover (ubiquitome analysis, SILAC, label-free proteomics and BONCAT). The PhD student will also learn how to design experiments and behavioural tasks and analyse biochemical and behavioural recording data, and write and review scientific manuscripts.

Rationale & hypothesis:

Eligibility: Applicants should meet the academic and English language entry requirements for admission to postgraduate programmes at the University of Edinburgh. Applicants should also 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).

Funding: This is a SIDB-funded award. It will provide an annual stipend for 3.5 years of £21,080 per annum, plus tuition fees (including international).

How to Apply: Please email Maria Corbi ([Email Address Removed]) to request an application form. Once you have completed the form you should return it direct, along with your references, to Maria at the same email address. Please contact Susana Louros ([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 3rd July 2024

Start time: The start time for the studentship is 9th September 2024.  

Biological Sciences (4)

Funding Notes

This is a SIDB funded award. It will provide an annual stipend for 3.5 years of £21,080 per annum, plus tuition fees (including international).


References

Louros SR*, Seo S *, Maio B, Martinez-Gonzalez C, Gonzalez-Lozano MA, Muscas M Verity NC, Wills JC, Li KW, Nolan MF and Osterweil EK. Excessive proteostasis contributes to the pathology in Fragile X Syndrome. Neuron 111, 1–18. https://doi.org/10.1016/j.neuron.2022.11.012

Where will I study?