Fairbrother-Browne, Áine Shelley; (2023) The role of mitochondrial-nuclear co-ordination in neurodegenerative disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Neurodegenerative diseases (NDs) are progressive neurological conditions that affect millions of people worldwide and yet there are few treatments that can prevent or slow progression. Mitochondrial dysfunction is known to contribute to the pathogenesis of an array of NDs, including Parkinson’s Disease (PD) and Alzheimer's disease (AD) for which the causal mechanisms, particularly in the sporadic forms, remain elusive. Mitochondrial processes have been implicated in the pathogenesis of both of these diseases. For mitochondria to carry out their diverse cellular roles, their interaction with the nucleus is essential, owing in part to the nuclear genome encoding 99% of the mitochondrial proteome. Although this bi-genomic interaction is widely acknowledged, there is little understanding about how this coordination may be important in NDs. In the first instance, mitochondrial-nuclear coordination in the healthy human brain was assayed by generating gene coexpression profiles across 12 regions, revealing strong regional patterns modulated by cell type and reflecting functional specialisation of the brain. Using an AD case-control paradigm, mitochondrial-nuclear relationships were found to be highly perturbed in cases, particularly through synaptic and lysosomal pathways, implicating energy balance regulation and removal of dysfunction mitochondria in the aetiology or progression of AD. Mitochondrial dysfunction is thought of as a core component of PD pathogenesis. In light of this, the subsequent aim was to characterise mitochondrial transcriptional profiles in monogenic familial PD, which has known genetic causes and better understood molecular mechanisms. Striking changes in oxidative phosphorylation (OXPHOS) subunit gene expression were observed in PD patients compared to controls, regardless of the underlying genetic cause (monogenic or sporadic). This was particularly marked in monogenic forms. Additionally, unsymptomatic monogenic PD profiles were more similar to those of symptomatic PD cases than to controls. As such, expression of OXPHOS pathway genes was found to be altered in PD, regardless of genetic cause or clinical status. This supports the idea that changes in mitochondrial processes may contribute to disease pathogenesis and points to these changes arising early in the progression trajectory. Building on these results, the final aim was to study mitochondrial transcriptional control in sporadic PD. Sporadic PD is characterised by its complex genetic origin and cryptic molecular mechanisms. To understand whether nuclear genetic variation modulated mitochondrial transcriptional phenotypes in sporadic PD, mitochondrial-nuclear expression QTLs and post-transcriptional (PT) modification QTLs were generated. This work leveraged the case-control, multi-omic AMP-PD consortium dataset (blood-derived RNA-Seq data from 1483 cases and 965 controls). Nuclear genetic regulation of mtDNA-encoded genes was found to be perturbed in PD, implicating MAP3K11 and CD9 in disease pathways that also operate through modulation of mitochondrial processes and pointing to a role for mitochondrial-nuclear co-ordination in the pathogenesis of sporadic PD.

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