Gillingwater, Tom

Faller, Kiterie

Mellanby, Richard

McHale-Owen, Harriet

Wellcome Trust

2026-05-28T12:11:53Z

2026-05-28

Metabolic dysfunction and cellular stress are common features in neurodegenerative conditions like motor neuron disease (MND) and supporting cell energy production is an attractive strategy to improve the resilience of neurons to disease pathology. Phosphoglycerate kinase 1 (PGK1) is a key enzyme in the first ATP-producing step in the glycolysis pathway. PGK1 may have multiple other roles in cells apart from its role in glycolysis but these are less well understood, and the consequences of increased PGK1 activity in cells and therefore its suitability as a therapeutic target is not known. Overexpression of PGK1 has been shown to be beneficial in multiple models of MND but the most commonly used PGK1 agonist, terazosin, is non-specific and so there is a need to develop more effective and more specific alternatives. In this thesis, I demonstrate that increased PGK1 activity in HEK-293 cells is well tolerated and does not result in the upregulation or downregulation of any cellular pathways supporting the further exploration of PGK1 agonists as potential future therapeutics. A metabolic assay in HEK-293 cells was used to identify the most promising PGK1 activators from a compound library. These lead compounds were then screened in a C9orf72 knockdown zebrafish model of MND. This work highlighted the importance of using a disease model for screening, as adding extra PGK1 to cells with adequate levels shows little observable effect. An alternative model is needed to test compounds for PGK1 activation more effectively. NSC-34 cell lines stably overexpressing human TDP-43 that are subjected to an osmotic stressor are a promising cell model to use for future assessments of potential PGK1 agonists. My work suggests that whilst PGK1 is a promising target, it is challenging to find suitable alternatives to terazosin. Future PGK1 studies should consider using stressed cellular models of disease as a screening method rather than traditional cell lines.

https://era.ed.ac.uk/handle/1842/44763

https://doi.org/10.7488/era/7278

en

McHale-Owen, H., K. M. E. Faller, H. Chaytow, and T. H. Gillingwater. 2025. 'Phosphoglycerate kinase 1 as a therapeutic target in neurological disease', Trends Mol Med.

Phosphoglycerate kinase 1 (PGK1)

PGK1

Motor neuron disease (MND)

MND

Therapeutic target

PGK1 agonists

Cell models

Phosphoglycerate kinase 1 as a therapeutic target in motor neuron disease

Thesis

Doctoral

PhD Doctor of Philosophy