Epigenetic Methylation and One-Carbon Metabolism in Human Motor Neuron Disease

TDP-43 proteinopathy is a histopathological hallmark of a class of neurodegenerative disorders termed ‘TDP-43 proteinopathies’, including motor neuron disease (MND) and frontotemporal lobar degeneration (FTLD). MND is an invariably fatal disorder involving the progressive degeneration of motor neurons, leading to loss of motor function and eventual death by respiratory failure. FTLD involves degeneration of the frontal and temporal lobes of the brain, resulting in cognitive, behavioural, and memory changes. Within disease-affected CNS regions, nearly all MND patients and half of all FTLD patients feature TDP-43 proteinopathy – nuclear loss, mislocalisation, and aggregation of the TDP-43 protein.

This thesis aims to investigate the relationship between TDP-43 proteinopathy and epigenetic methylation processes, with a focus on DNA methylation in MND. Immunohistochemical analysis finds consistent significant relationships between TDP-43 proteinopathy and hypomethylation of two epigenetic methylation markers (5mC for DNA methylation, and H3K27me3) across different TDP-43 proteinopathy-vulnerable CNS regions post-mortem.

This study also explores the metabolic pathways influencing methylation – one-carbon metabolism (composed of the methionine cycle, folate cycle, and transsulfuration pathway), finding evidence of dysregulation of two core metabolites in MND brain tissue post-mortem: s-adenosylmethionine and cystathionine.

A cellular model of inducible TDP-43 proteinopathy was developed for further mechanistic exploration of these relationships, which recapitulated the relationship between DNA hypomethylation and TDP-43 proteinopathy. Treatment of this cell model with s-adenosylmethionine and cystathionine showed prevention of TDP-43 proteinopathy formation.

To conclude, this thesis presents evidence of a relationship between TDP-43 proteinopathy and hypomethylation of epigenetic methylation, and evidence for one-carbon metabolism dysregulation that may contribute to this. Additionally, this thesis highlights the possible therapeutic avenues of manipulating one-carbon metabolism and epigenetic methylation to target TDP-43 proteinopathy.