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Experimental analysis of a genetic modifier of ALS(amyotrophic lateral sclerosis)/FTD (frontotemporal dementia)

  • Full or part time
    Prof L Partridge
    Prof Adrian Isaacs
  • Application Deadline
    Wednesday, April 03, 2019
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Amyotrophic lateral sclerosis (ALS – sometimes known as motor neuron disease) and frontotemporal dementia are devastating neurological diseases with no current preventative or curative measures available. Some cases are familial, and attributable to a highly expanded, hexanucleotide repeat in the C9orf72 gene. Loss of function of C9orf72 could cause toxicity but, although this may contribute, the major problem seems to be the repeat sequence itself. It is transcribed into RNA in both directions, and the transcripts are translated into proteins in all reading frames, producing 5 different dipeptide repeat proteins (DPRs). Our own work, and that of others, has strongly suggested that the two arginine-containing DPRs are particularly toxic. We are trying to find out how to prevent this toxicity.

We have performed a genetic screen in the fruit fly Drosophila for genes that can rescue this toxicity. A top hit, with a strong rescue effect, encodes a transcription factor, which controls expression of other genes and which also has mammalian orthologs. This is an exciting finding, because these transcription factors have not previously been implicated in neuronal survival or protection against neurodegenerative disease. The aim of this project is to investigate how this rescue of toxicity happens, and the implications for therapeutic opportunities. The scientific environment for the student will provide an ideal training in neuroscience and experimental approaches to dementia.

Funding provided by Alzheimer’s Research UK (ARUK)

Interviews will be held on Friday, 12th April 2019. The studentship will commence in September 2019.

To apply please click on the ’Email Now’ button and attach a single document containing your CV and a covering letter. Enquiries can be addressed to Michael Wright, Executive Officer, Institute of Healthy Ageing at

Funding Notes

ARUK provide a student stipend of £17,000 per annum plus tuition fees at Home/EU rate and research/travel costs.

Studentship is open to UK/EU students only.

English language criteria apply.

Applicants are required to hold a first or upper-second class UK Bachelor’s degree in an appropriate subject, or a recognised Master’s degree.

References

DeJesus-Hernandez, M., et al., Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron, 2011. 72(2): p. 245- 56.

Renton, A.E., et al., A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron, 2011. 72(2): p. 257-68.

Moens, T.G., L. Partridge, and A.M. Isaacs, Genetic models of C9orf72: what is toxic? Curr Opin Genet Dev, 2017. 44: p. 92-101.

Balendra, R. and A.M. Isaacs, C9orf72-mediated ALS and FTD: multiple pathways to disease. Nat Rev Neurol, 2018. 14(9): p. 544-558.

Mori, K., et al., The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science, 2013. 339(6125): p. 1335-8.

Ash, P.E., et al., Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron, 2013. 77(4): p. 639-46.

Mizielinska, S., et al., C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science, 2014. 345(6201): p. 1192-1194.

Alic, N., et al., Genome-wide dFOXO targets and topology of the transcriptomic response to stress and insulin signalling. Mol Syst Biol, 2011. 7: p. 502.

Castillo-Quan, J.I., et al., Lithium Promotes Longevity through GSK3/NRF2-Dependent Hormesis. Cell Rep, 2016. 15(3): p. 638-650.

How good is research at University College London in Biological Sciences?
(joint submission with Birkbeck College)

FTE Category A staff submitted: 172.90

Research output data provided by the Research Excellence Framework (REF)

Click here to see the results for all UK universities

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