Investigating genetic modifiers of Huntington’s disease using Drosophila melanogaster

Sadler, Freja 2022. Investigating genetic modifiers of Huntington’s disease using Drosophila melanogaster. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Huntington’s disease is an autosomal dominant neurodegenerative disease which is caused by the pathological expansion of the CAG repeat tract in the huntingtin gene (HTT). The age at which symptoms onset is inversely correlated with the CAG repeat tract length, but other factors such as genetic variation can also influence the onset. Genome-wide association studies have identified genetic variants in the loci of genes that function in DNA damage responses. Specifically, genes associated with the DNA mismatch repair pathway and DNA interstrand cross-link repair are thought to affect the age of onset by somatically expanding the CAG repeat tract. However, CAG repeat expansion is not the only driver of disease progression with other potential modifiers being missed by the GWAS. This thesis demonstrates that Drosophila melanogaster pan-neuronally expressing mutant human HTT exhibit shortened lifespans, locomotor deficits, HTT aggregation and neurodegeneration. There was no evidence of somatic instability of the CAG repeat tract in HTT expressed in Drosophila neurons, which meant potential modifiers of HD could be investigated without the having to consider CAG repeat instability. Potential genetic modifiers of the locomotor phenotype were screened and Parp knockdown significantly improved the locomotor performance of mutant HTT expressing flies. Parp knockdown and inhibition was characterised further in the different Drosophila models of HD it was established that reducing Parp expression and inhibiting Parp with pharmacological inhibitors ameliorated lifespan, locomotor and HTT aggregation phenotypes. The results suggest a potentially promising future for PARP1 inhibition in HD treatment.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	17 January 2023
Last Modified:	17 Jan 2024 02:30
URI:	https://orca.cardiff.ac.uk/id/eprint/155955

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