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

Background 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 dys-regulated energy metabolism, linked to multiple neurodegenerative diseases including ALS. Methods Activity of the glycolysis enzyme phosphoglycerate kinase 1 (PGK1) was increased genetically or pharmaco-logically using terazosin in zebrafish, mouse and ESC-derived motor neuron models of ALS. Multiple disease pheno-types were assessed to determine the therapeutic potential of this approach, including axon growth and motor behaviour, survival and cell death following oxidative stress. Findings 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 res-cuing stress granule assembly. Interpretation 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. Copyright (C) 2022 The Author(s). Published by Elsevier B.V.

Automated summary

The study demonstrates that modulating the activity of the glycolysis enzyme PGK1 can improve motor neuron function in models of amyotrophic lateral sclerosis (ALS). Treatment with terazosin, which increases PGK1 activity, extends survival, improves motor phenotypes, and protects against oxidative stress-induced cell death. This research provides a new potential approach for ALS therapy.