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Published on: October 6, 2015
Targeting phosphoglycerate kinase 1 with terazosin improves motor neuron phenotypes in multiple models of amyotrophic
Helena Chaytow1, Emily Carroll2, David Gordon2
1Edinburgh Medical School: Biomedical Sciences, University of Edinburgh; Edinburgh, UK; Euan MacDonald Centre for Motor Neuron Disease Research; Edinburgh, UK.
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 dysregulated energy metabolism, linked to multiple neurodegenerative diseases including ALS.
Methods:
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.
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 rescuing 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.
Funding:
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 [SGL023\1100].
Insights
The drug terazosin boosts glycolysis by targeting phosphoglycerate kinase 1 (PGK1), offering a potential new treatment for amyotrophic lateral sclerosis (ALS) by protecting motor neurons.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with complex genetics.
- Dysregulated energy metabolism is a common pathway in neurodegenerative disorders, including ALS.
- Targeting convergent pathways may offer effective therapeutic strategies for ALS.
Purpose of the Study:
- To investigate the therapeutic potential of targeting phosphoglycerate kinase 1 (PGK1) in ALS models.
- To evaluate the efficacy of terazosin, a drug that increases PGK1 activity, in ALS.
- To explore the mechanisms by which PGK1 modulation affects motor neuron survival and function.
Main Methods:
- Increased phosphoglycerate kinase 1 (PGK1) activity genetically and pharmacologically (terazosin) in zebrafish, mouse, and human motor neuron models of ALS.
- Assessed motor neuron phenotypes, including axon growth, motor behavior, survival, and cell death.
- Investigated the impact of terazosin on glycolysis rates and stress granule formation.
Main Results:
- Overexpression of PGK1 in zebrafish models rescued motor axon defects and improved behavior.
- Terazosin treatment improved motor phenotypes, extended survival, and increased motor neuron numbers in mouse models.
- In human motor neurons, terazosin protected against oxidative stress, enhanced glycolysis, and reduced stress granule assembly.
Conclusions:
- Targeting PGK1 modulates motor neuron vulnerability in ALS.
- Terazosin protects motor neurons through increased glycolysis and reduced stress granule formation.
- Repurposing terazosin presents a promising therapeutic avenue for all forms of ALS.
