Hicks, Amy Rose Edith; (2024) Investigating the Role of the Non-Specific Lethal (NSL) Complex in Modifying Genes and Pathways Associated with Parkinson's Disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Genetic variants conferring risk for Parkinson’s disease (PD) have been highlighted through genome wide association studies (GWASs), yet exploration of their specific disease mechanisms is lacking. Two PD candidate genes, KAT8 and KANSL1, identified through genome-wide studies and a PINK1-mitophagy screen, encode part of the histone acetylating Non-Specific Lethal (NSL) complex. This complex localises primarily to the nucleus, where it has a role in transcriptional activation. This thesis aims to identify and evaluate potential gene regulatory relationships between the NSL complex and genes and pathways associated with PD. Firstly, I have examined gene co-expression networks (GCNs) produced from publicly available transcriptomic data from human brain. I found significant clustering of NSL genes alongside PD-associated genes within modules enriched for mainly neuronal cell types. I then generated a NSL complex regulon and found it contained PD-associated genes, was enriched for biological pathways genetically-linked to PD and was partially validated in a neuroblastoma cell line. Secondly, I have compared bulk ribonucleic acid (RNA)-sequencing data from wildtype neuroblastoma cells with KAT8 and KANSL1 short interfering RNA (siRNA) knockdown (KD). I found KANSL1 KD in particular altered the expression of genes associated with PD, as well as lysosomal genes targeted by transcriptional regulator, TFEB. Public Chromatin Immuno-Precipitation (ChIP)-sequencing data indicated direct binding of KANSL1 to several PD-associated and lysosomal genes. Thirdly, I examined the regulatory activity of haplotype variation at the KANSL1/17q21.31 locus on gene expression across the genome. Bulk RNA-sequencing data from control and PD patient brains indicated upregulation of pathways involved in the immune system in the protective H2 haplotype, whilst single-nuclear data suggested these relationships to be most important in astrocyte cells. These findings provide a map of the transcriptomic differences between 17q21.31 haplotypes in both controls and patients diagnosed with PD. In conclusion, these findings reveal a wider role for the NSL complex in regulating the expression of genes implicated in PD that is particularly driven by the control of lysosomal and immune pathways.

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