MRC DiMeN Doctoral Training Partnership: Decoding Shank3: New Insights into neuronal maintenance and neurodegeneration via structural analysis and Drosophila models

Description

As we age, neurons deteriorate. This is often accelerated by mutations in proteins associated with neurological disorders. Shank3 is a key protein in the synapse, where it supports the assembly of postsynaptic density critical for synaptic transmission. Mutations in the SHANK3 gene are associated with several neurodevelopmental disorders, such as autism, schizophrenia, and bipolar disorder. Recent evidence suggests that Shank3 also plays a vital role in neuron maintenance during ageing, and in patients with Alzheimer's disease (AD) protein levels are altered. However, the precise molecular mechanisms linking Shank3 dysfunction to age-related neurodegeneration are currently poorly understood. This project aims to explore these mechanisms and provide new insights into how Shank3 mutations impact neuronal integrity, synaptic function, and age-related decline. This information is critical for the development of future treatments for neurodegenerative disorders and for the improvement of the neuronal health at the later stages of life.

The first objective of this project will focus on investigating the molecular properties of Shank3 that contribute to its stability and function. Using advanced biochemical techniques such as Nuclear Magnetic Resonance (NMR) and Dynamic Light Scattering, we will analyse how different domains of Shank3 interact and how certain mutations destabilize the protein. We hypothesize that some mutations cause the protein to aggregate in neurons, underlying neurodegeneration.

The second objective will build on this molecular analysis and explore how these changes manifest in living neurons. Using genetically modified Drosophila models that express mutated Shank3, we will observe the protein distribution and behaviour within neurons. Our preliminary data suggest that certain mutations lead to abnormal accumulations of Shank3 aggregates along axons, which could impair neuronal communication. By studying the effect of Shank3 on neuronal health, we will determine whether mutations in Shank3 cause a loss of normal function or if the aggregates themselves are toxic to neurons.

Finally, in the third objective, we will examine the larger-scale effects of Shank3 mutations on neuronal networks and synaptic integrity in Drosophila models of ageing and AD. Using high-resolution imaging and 3D brain reconstruction, we will assess how Shank3 dysfunction affects neuron morphology and synaptic connections over time. This will help us to understand whether the protein instability accelerates age-related neurodegeneration, potentially offering new therapeutic targets for AD and other neurodegenerative disorders.

This multidisciplinary project will provide the candidate with hands-on experience in biochemical, genetic, and imaging techniques, offering a unique opportunity to work at the cutting edge of neurodegeneration research. Through lab rotations you will gain research expertise and interact closely with researchers from diverse fields of the supervisors: structural biology and biochemistry (I.Barsukov, https://www.liverpool.ac.uk/systems-molecular-and-integrative-biology/staff/igor-barsukov/research/), and cell biology, neuronal imaging and Drosophila models of ageing and AD (N.Sanchez Soriano, https://sanchezlab.wordpress.com/).

Benefits of being in the DiMeN DTP:

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, York 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, training opportunities or internships in science policy, science communication and beyond. Further information on the programme and how to apply can be found on our website:

https://www.dimen.org.uk/