EMC-2024-2_Grant and Selvaraj: Repairing synapse damage in MND


   Centre for Clinical Brain Sciences

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  Prof S Grant, Dr Bhuvaneish Thangaraj Selvaraj  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

This project is on offer as part of the studentship scheme of the Euan MacDonald Centre for Motor Neuron Disease Research. The Euan MacDonald Centre is a multi-disciplinary network of MND researchers across Scotland. A choice of six projects is on offer now for a start date in Autumn 2024, at the University of Edinburgh, St Andrews or Dundee. For more information see www.euanmacdonaldcentre.org/phd-scheme. Euan MacDonald Centre students join our network of >200 MND researchers across Scotland and will have the opportunity to meet people living with MND, participate in academic and public engagement events led by the Centre. To view all the projects offered under this scheme please search for reference numbers EMC-2024-1 to EMC-2024-6.

Synapse loss and damage are key features of neurodegenerative diseases including Motor Neuron Disease (MND). Recent advancements in molecular imaging techniques have unveiled a far greater spectrum of synapse types than previously recognised. These synapse types exhibit a remarkable organization, distributed across nerve cells, various brain regions, and the entire brain. Importantly, we have identified specific synapse types that are susceptible to damage in neurological disorders, while others exhibit resistance. While the reduction of synapses in neurodegenerative conditions is well-documented, we have limited knowledge regarding the characteristics of vulnerable and resilient synapses and their role in MND. Furthermore, we have scarce insights into strategies for promoting synapse resilience and repairing damaged synapses in MND.

To tackle these challenges, we will leverage the combined expertise of two research groups. Grant's pioneering methods for identifying vulnerable and resilient synapses in the spinal cord and brain of humans will be paired with Selvaraj's platforms for generating human stem cell derived cortical and spinal organoids that produce an abundance of synapses tractable for temporal studies. Initially, we will categorize the synapse types within organoids obtained from control subjects and those with MND (TDP43 and C9ORF72 mutation). This will validate the utility of organoids for in vitro analysis of synapse-related issues and enable the identification of "MND-vulnerable synapses." Subsequently, we will develop a scalable platform for assessing therapeutic interventions designed to target these synapse to boost their resilience and abundence. The project will be highly integrative, provide training in a wide range of biological and computational methods and draw upon unique expertise and resources in Edinburgh University.

Suitable first degree subjects: Molecular biology, cell biology, biotechnology, neuroscience. Essential and/or desirable skills and experience: Desirable: wetlab laboratory experience including mammalian cell culture, immunolabelling.

Biological Sciences (4) Medicine (26)

Funding Notes

The studentship comprises 42 months (3.5 years) stipend payments at the standard UKRI rate, tuition fees and an allowance of £10K per year for three years for consumables and travel. The studentship is open to applicants worldwide. Students will register for the most appropriate degree programme at the University where the project is being offered. It is the applicants’ responsibility to ensure they meet the eligibility requirements for postgraduate study at their chosen University, in terms of academic achievements and English language proficiency.

References

1. Broadhead, M. J., et al. "Selective vulnerability of tripartite synapses in amyotrophic lateral sclerosis." Acta Neuropathol, doi:10.1007/s00401-022-02412-9 (2022).
2. Cizeron, M., et al. "A brainwide atlas of synapses across the mouse life span." Science 369, 270-275, doi:10.1126/science.aba3163 (2020).
3. Curran, O. E., Qiu, Z., Smith, C., & Grant, S. G. N. "A single-synapse resolution survey of PSD95-positive synapses in twenty human brain regions." Eur J Neurosci, doi:10.1111/ejn.14846 (2020).
4. James, O. G., Selvaraj, B. T., et al. "iPSC-derived myelinoids to study myelin biology of humans." Dev Cell 2021 May 3;56(9) doi: 10.1016/j.devcel.2021.04.006.
5. Mehta, et al. "Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis." Acta neuropathol 2021 Feb;141(2):257-279. doi: 10.1007/s00401-020-02252-5.

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