Analysis of genetic and protein interactions associated with mutant Huntingtin-induced degeneration

Spicer, Rachel 2024. Analysis of genetic and protein interactions associated with mutant Huntingtin-induced degeneration. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

FoxP1 and Mef2C are two genes important for mouse striatal development, the brain region that is most vulnerable the effects of the mutated protein responsible for Huntington’s Disease (HD), Huntingtin (HTT). Using Drosophila and mouse models of HD, I have investigated the effects of manipulating these two genes and showed that they can suppress mutant HTT(mHTT)-induced degeneration. Prior to this project, studies had shown that a Mef2 isoform, Mef2D, could physically interact with mHTT and that a chromosomal deficiency, which included the single Drosophila Mef2 gene, could suppress whole-eye mHTT-induced degeneration. However, research had not investigated whether the Mef2 gene was responsible for this observation, or how this might be translated to the human HD condition. Utilising the Gal4/UAS system, I showed that downregulating the Drosophila Mef2 gene can suppress mHTT-induced degeneration in a whole-eye and pan-neuronal model of HD. I also showed that over-expressing the N-terminal fragment of FoxP1 in a Drosophila HD model can suppress mHTT-induced degeneration. I generated a novel mouse line which expressed that R6/1 transgene with striatal knockout of Mef2C, a concept that had not been investigated prior to this project. I showed that striatal Mef2C knockout in the R6/1 brain significantly reduces the number of mHTT inclusions in the striatum. These mice also performed better on the balance beam task. Finally, using the Gal80tsGal4/UAS system, I show that pre-exposure of neurons to mHTT during development of the Drosophila eye leads to enhanced vulnerability and early cell death of photoreceptor neurons, which is not seen when inducing mHTT in the fully developed eye. In this work, I utilised Drosophila HD models to further our understanding of the role of Mef2C and FoxP1 in mHTT-induced degeneration and translated this research into a novel mouse model to investigate Mef2C downregulation in a complex mammalian model.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	19 November 2024
Date of Acceptance:	19 November 2024
Last Modified:	19 Nov 2024 11:06
URI:	https://orca.cardiff.ac.uk/id/eprint/174133

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