Costa, Beatrice; (2022) Integration of in silico and in vitro approaches to investigate genetic and functional drivers of frontotemporal lobar degeneration. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Frontotemporal lobar degeneration (FTLD) is a common form of early-onset dementia presenting with a complex gene and pathological architecture. Impairment in several molecular pathways has been associated with FTLD pathology however translating genetic knowledge into functional understanding of impacted biological processes in complex disorders still represents a major challenge. This thesis proposes a multi-omics network approach integrating genetics, transcriptomics and proteomics to investigate the common pathogenic mechanisms and their associated genes/proteins underlying Mendelian and sporadic forms of FTLD. Protein-protein interaction (PPINs) and gene co-expression (GCNs) networks were used to prioritise: i) disease-specific biological processes on the basis of known FTLD Mendelian and GWAS genes and ii) their associated genes/proteins, which were carried forward for hypothesis-driven functional validation using in vitro cellular models. A separate study specifically investigated C9ORF72 repeat expansions (i.e., a common genetic signature of FTLD) as a potential genetic modifier of FTLD syndromes in relation to genetic ancestry and age at onset (AAO). Results from these studies revealed that waste disposal, and autophagy/mitophagy dysfunction in particular, are among the most relevant biological processes impacted in FTLD. Further work indicated that CDC37, protein with no reported link to the mitochondria, has an important role in modulating PINK1-dependent mitophagy, as CDC37 deficient cells exhibited an increase in both PINK1 mRNA and protein expression as well as PINK1-dependent phosphorylation of ubiquitin, a common marker of mitophagy; additionally, CDC37 deficiency was shown to increase transcriptional expression of GRN, a common FTLD Mendelian gene. Finally, an iPSC GRN-/- model showed that both CDC37 protein expression and mitophagy were downregulated upon GRN insufficiency, suggesting a shared mechanism between GRN, PINK1 and CDC37 where GRN modulation might be regulating the trafficking and stability of PINK1 via CDC37. Additionally, C9ORF72 analyses indicated a correlation between pathogenic C9ORF72 expansions, AAO, principal component analysis (PCA)-based Central/Northern European ancestry, and a diagnosis of bvFTLD, implying complex genetic risk architectures differently underpinning the behavioural and language variant syndromes. These findings contribute to our understanding of PINK1-dependent mitophagy regulation via CDC37 and GRN and further emphasise the relevance of autophagy/mitophagy dysfunction in FTLD.

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