The PHA1 risk gene and its Alzheimer’s Disease associated variants

Thorburn, Lauren 2022. The PHA1 risk gene and its Alzheimer’s Disease associated variants. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Alzheimer’s disease (AD) is a progressive neurological disorder. Genetic studies have identified numerous risk or susceptibility genes/loci to be linked to the pathology of late onset AD. One such gene is the EphA1 receptor which contains numerous genetic variants within the introns of the gene or within its neighbouring EPHA1-AS1 antisense gene. Genomic location and inheritance pattern of the variants make identifying the causal variant behind a loci’s disease association difficult, requiring the overlay of both bioinformatic and functional data onto genetic data. Two EPHA1 variants rs11765305 and rs7810606 were found to have the ability to affect the binding affinity of nuclear proteins. Deletion of these variants resulted in increased expression of the ZYX gene, a loss of stemness morphology and a decrease in pluripotency genes was also noted. Bioinformatic analysis hints at the CEBPB, KLF family or EGR1 transcription factors being involved in the alterations to ZYX regulation observed. It is likely that these variants are behind the EPHA1 loci’s association with AD, through altered regulation of ZYX contributing to disease pathology such as inflammation and synaptic impairment. A coding variant within the EphA1 receptor P460L has been linked to late onset AD. The exact role of the EphA1 receptor during AD and how alterations as a consequence of P460L affect disease progression is unknown. This thesis identified both reduced receptor membrane expression and reduced soluble receptor release as a result of the P460L variant. Transient serine residue dephosphorylation followed by tyrosine residue phosphorylation was noted upon ligand activation of the EphA1 receptor. However, subsequent increase in phosphotyrosine was not observed within the P460L mutant. This reduced receptor membrane expression and subsequent activity due to the P460L variant may impact any role the EphA1 receptor may play within the periphery or brain that may regulate AD.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	27 February 2023
Last Modified:	27 Feb 2024 02:30
URI:	https://orca.cardiff.ac.uk/id/eprint/157380

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