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Investigating human stem cell-derived cortical neurons with the G51D a-synuclein mutation as a model for dementia with Lewy bodies

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  • Full or part time
    Dr T Kunath
    Dr M Zagnoni
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Dementia with Lewy bodies (DLB) is the second most common type of dementia after Alzheimer’s. It is characterised by a-synuclein-positive inclusions in the cortex called Lewy bodies. Recently, a family with a G51D mutation in alpha-synuclein (aSyn) was reported to have severe DLB, as well as parkinsonism (1). We have derived induced pluripotent stem cells (iPSCs) from a member of this family with the G51D mutation, and also published iPSCs from a patient with triplication of the a-synuclein gene who also suffered from DLB (2).
This PhD project with differentiate the DLB patient iPSCs into cortical neurons using a highly efficient protocol to investigate primary disease mechanisms caused by (i) G51D, and (ii) over-production of aSyn. The neurons will be differentiated in custom-designed microfluidics devices in collaboration with Dr Michele Zagnoni (University of Strathclyde), an expert in lab-on-chip applications for neuroscience and stem cell-derived neurons (3,4). Questions to address include: (i) Does G51D-aSyn aggregate in human stem cell-derived neurons? (ii) Does G51D-aSyn transfer pathology from neuron-to-neuron more efficiently than WT-aSyn? (iii) Which proteins are mis-regulated in G51D-aSyn stem cell-derived neurons, and (iv) Can small molecules reduce or eliminate G51D-aSyn induced defects in human cortical neurons?

Funding Notes

This is part of a competition studentship with project 2020-CCBS-05 (see https://www.edinburghneuroscience.ed.ac.uk/project/dementia-including-alzheimers-disease-neurodegeneration/investigation-mechanisms). The best applicant will be offered the studentship, regardless of which project they wish to do. You can apply to both projects, but this will not offer any advantage.

The studentship includes a 3 year UKRI-level stipend, UK/EU level tuition fees, and an allowance for consumables and travel. The project would suit applicants with a background in basic neuroscience, developmental biology and molecular biology.

References

1. Kiely AP, Asi YT, Kara E, Limousin P, Ling H, Lewis P, Proukakis C, Quinn N, Lees AJ, Hardy J, Revesz T, Houlden H, Holton JL. (2013) α-Synucleinopathy associated with G51D SNCA mutation: a link between Parkinson's disease and multiple system atrophy? Acta Neuropathol. 125:753-69.
2. Devine MJ, Ryten M, Vodicka P, Thomson AJ, Burdon T, Houlden H, Cavaleri F, Nagano M, Drummond NJ, Taanman JW, Schapira AH, Gwinn K, Hardy J, Lewis PA, Kunath T. (2011) Parkinson's disease induced pluripotent stem cells with triplication of the α-synuclein locus. Nat Commun. 2:440.
3. Sposito T, Preza E, Mahoney CJ, Setó-Salvia N, Ryan NS, Morris HR, Arber C, Devine MJ, Houlden H, Warner TT, Bushell TJ, Zagnoni M, Kunath T, Livesey FJ, Fox NC, Rossor MN, Hardy J, Wray S. (2015) Developmental regulation of tau splicing is disrupted in stem cell-derived neurons from frontotemporal dementia patients with the 10 + 16 splice-site mutation in MAPT. Hum Mol Genet. 24:5260-9.
4. MacKerron C, Robertson G, Zagnoni M, Bushell TJ. (2017) A Microfluidic Platform for the Characterisation of CNS Active Compounds. Sci Rep. 7:15692.

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FTE Category A staff submitted: 117.28

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