PUBLICATION

Targeting phosphoglycerate kinase 1 with terazosin improves motor neuron phenotypes in multiple models of amyotrophic lateral sclerosis

Authors
Chaytow, H., Carroll, E., Gordon, D., Huang, Y.T., van der Hoorn, D., Smith, H.L., Becker, T., Becker, C.G., Faller, K.M.E., Talbot, K., Gillingwater, T.H.
ID
ZDB-PUB-220815-1
Date
2022
Source
EBioMedicine   83: 104202 (Journal)
Registered Authors
Becker, Catherina G., Becker, Thomas
Keywords
Bioenergetics, Drug repurposing, Motor neuron disease (MND), Neuroprotection
MeSH Terms
  • Amyotrophic Lateral Sclerosis*/drug therapy
  • Amyotrophic Lateral Sclerosis*/genetics
  • Amyotrophic Lateral Sclerosis*/metabolism
  • Animals
  • DNA-Binding Proteins/genetics
  • Humans
  • Mice
  • Motor Neurons/metabolism
  • Phenotype
  • Phosphoglycerate Kinase/genetics
  • Phosphoglycerate Kinase/metabolism*
  • Prazosin/analogs & derivatives
  • Zebrafish/metabolism
PubMed
35963713 Full text @ EBioMedicine
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with heterogeneous aetiology and a complex genetic background. Effective therapies are therefore likely to act on convergent pathways such as dysregulated energy metabolism, linked to multiple neurodegenerative diseases including ALS.
Activity of the glycolysis enzyme phosphoglycerate kinase 1 (PGK1) was increased genetically or pharmacologically using terazosin in zebrafish, mouse and ESC-derived motor neuron models of ALS. Multiple disease phenotypes were assessed to determine the therapeutic potential of this approach, including axon growth and motor behaviour, survival and cell death following oxidative stress.
We have found that targeting a single bioenergetic protein, PGK1, modulates motor neuron vulnerability in vivo. In zebrafish models of ALS, overexpression of PGK1 rescued motor axon phenotypes and improved motor behaviour. Treatment with terazosin, an FDA-approved compound with a known non-canonical action of increasing PGK1 activity, also improved these phenotypes. Terazosin treatment extended survival, improved motor phenotypes and increased motor neuron number in Thy1-hTDP-43 mice. In ESC-derived motor neurons expressing TDP-43M337V, terazosin protected against oxidative stress-induced cell death and increased basal glycolysis rates, while rescuing stress granule assembly.
Our data demonstrate that terazosin protects motor neurons via multiple pathways, including upregulating glycolysis and rescuing stress granule formation. Repurposing terazosin therefore has the potential to increase the limited therapeutic options across all forms of ALS, irrespective of disease cause.
This work was supported by project grant funding from MND Scotland, the My Name'5 Doddie Foundation, Medical Research Council Doctoral Student Training Fellowship [Ref: BST0010Z] and Academy of Medical Sciences grant [SGL023H0].
Genes / Markers
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