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MRC DiMeN Doctoral Training Partnership: Why do SHANK3 mutations contribute to autism: finding the answers with protein structures, cultured neurons and Drosophila models


MRC DiMeN Doctoral Training Partnership

Liverpool United Kingdom Biochemistry Bioinformatics Biophysics Cell Biology Data Analysis Neurology Neuroscience Structural Biology

About the Project

Background

Understanding how brain works is a major challenge for modern biology. Synapses are the main points of communications between neurons, creating billions of smart connections that dynamically change in development and learning. The “signal processing machine” of synapses is located within the postsynaptic density (PSD) composed of a dense network of inter-connected proteins. In a healthy brain molecular interaction within PSD are finely balanced, allowing it to change in response to synaptic activation. This balance is affected in neurological disorders, such as the increasingly common Autism Spectrum Disorder (ASD).  

Autism affects 1/300 of the population and care costs ~$4.7 million per person.  Currently there is no cure for autism, primarily because we do not understand sufficiently molecular processes in synapses. Solving the brain mysteries and applying this knowledge in medicine will require a multi-disciplinary approach, including cutting edge molecular, cellular and organism-based experiments.

SHANK3 is one of the key proteins in synapses that affect brain development. It belongs to a small group of proteins associated with high ASD risk. Many SHANK3 mutations have been deposited into genetics databases and new mutations are constantly discovered in patients. Mouse and other animal models demonstrate ASD-like behaviour when SHANK3 is mutated or deleted but the underlying mechanisms remain unclear. Understanding how SHANK3 mutations change the protein properties and contribute to ASD has the potential to find new drug targets.

Project aims

In this multi-disciplinary, collaborative project you will study the effect SHANK3 mutations on its protein structure and function in neurons. Experiments in the fruit fly (Drosophila) and in brain-derived mouse cell lines will help to relate the structural changes of the protein to their function in vivo and in cells. Drosophila is a validated an established ASD model and not only helps to avoid experiments with mammals but also has only one SHANK isoform, which facilitates analysis of mutations.

In our previous research we discovered a direct connection of SHANK3 to the fundamental signalling pathways controlled by Ras and Rap GTPases that regulate synaptic processes. This led to hypothesis that SHANK3 mutations disrupt the optimal signalling, causing abnormal synaptic structure and function. You will use Nuclear Magnetic Resonance (NMR) and X-ray crystallography to investigate changes in SHANK3 structure and interactions caused by the mutations. From this information you will design molecular probes and use advanced fluorescent microscopy in living neurons to investigate how SHANK3 changes affect structure and development of synapses. The diverse information gained in this project aims to solve the mystery of how SHANK3 mutations contributes to autism. The new knowledge will contribute to future prevention and treatment of neurodegenerative diseases. 

Training

The project offers a unique opportunity to master advanced methods of bioinformatics, structural biology and high-resolution fluorescent microscopy, and apply them to study cultured neurons and Drosophila animal models that are widely used in medical research. Through lab rotations you will closely interact with researchers from diverse fields of your three supervisors: structural biology (I.Barsukov, https://www.liverpool.ac.uk/integrative-biology/staff/igor-barsukov/), cell imaging (C.Ballestrem, https://www.research.manchester.ac.uk/portal/christoph.ballestrem.html) and Drosophila biology (N.Sanchez Soriana, https://sanchezlab.wordpress.com/).

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards

Further information on the programme and how to apply can be found on our website:

https://bit.ly/3lQXR8A 


Funding Notes

Studentships are funded by the Medical Research Council (MRC) for 3.5yrs. Funding will cover UK tuition fees and stipend only. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme. Please read additional guidance here: View Website
Studentships commence: 1st October 2021
Good luck!

References

1. Lilja J, Zacharchenko T, Georgiadou M, Jacquemet G, De Franceschi N, Peuhu E, Hamidi H, Pouwels J, Martens V, Nia FH, Beifuss M, Boeckers T, Kreienkamp HJ, Barsukov IL, Ivaska J. (2019) SHANK proteins limit integrin activation by directly interacting with Rap1 and R-Ras. Nat Cell Biol. 19(4):292-305.
2. Melero, C., Kolmogorova, A., Atherton, P., Derby, B., Reid, A., Jansen, K. & Ballestrem, C. (2019) Light-Induced Molecular Adsorption of Proteins Using the PRIMO System for Micro-Patterning to Study Cell Responses to Extracellular Matrix Proteins, Journal of visualized experiments : JoVE. 152
3. Voelzmann, A., Okenve Ramos, P., Qu, Y., Chojnowska-Monga, M., del Caño-Espinel, M., Prokop, A., Sánchez-Soriano, N. (2016). Tau and spectraplakins promote synapse formation and maintenance through Jun kinase and neuronal trafficking. eLife 5, e14694.

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