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  3. Pharmacological inhibition of the integrated stress response accelerates disease progression in an amyotrophic lateral sclerosis mouse model

Pharmacological inhibition of the integrated stress response accelerates disease progression in an amyotrophic lateral sclerosis mouse model

  • Br J Pharmacol. 2024 Feb;181(3):495-508. doi: 10.1111/bph.16260.
Elías Marlin 1 2 3,  Miguel Valencia 2 3 4,  Nuria Peregrín 1 2,  Roberto Ferrero 1 3,  María Jesús Nicolás 2 3,  Rodrigo Vinueza-Gavilanes 1 2 3,  Antonio Pineda-Lucena 5,  Julio Artieda 3 6 7,  Montserrat Arrasate 1 2 3 7,  Tomás Aragón 1 3
Affiliations

Affiliations

  • 1 Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
  • 2 Neuroscience Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
  • 3 Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.
  • 4 Institute of Data Science and Artificial Intelligence (DATAI), University of Navarra, Pamplona, Spain.
  • 5 Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
  • 6 Department of Neurology, Clínica Universidad de Navarra, University of Navarra, Pamplona, Spain.
  • 7 School of Medicine, University of Navarra, Pamplona, Spain.
PMID: 37823684 DOI: 10.1111/bph.16260
Abstract

Background and purpose: The integrated stress response (ISR) regulates translation in response to diverse stresses. ISR activation has been documented in amyotrophic lateral sclerosis (ALS) patients and ALS experimental models. In experimental models, both ISR stimulation and inhibition prevented ALS neurodegeneration; however, which mode of ISR regulation would work in patients is still debated. We previously demonstrated that the ISR modulator ISRIB (Integrated Stress Response InhiBitor, an eIF2B activator) enhances survival of neurons expressing the ALS neurotoxic allele SOD1 G93A. Here, we tested the effect of two ISRIB-like eIF2B activators (2BAct and PRXS571) in the disease progression of transgenic SOD1G93A mice.

Experimental approach: After biochemical characterization in primary neurons, SOD1G93A mice were treated with 2BAct and PRXS571. Muscle denervation of vulnerable motor units was monitored with a longitudinal electromyographic test. We used a clinical score to document disease onset and progression; force loss was determined with the hanging wire motor test. Motor neuronal survival was assessed by immunohistochemistry.

Key results: In primary neurons, 2BAct and PRXS571 relieve the ISR-imposed translational inhibition while maintaining high ATF4 levels. Electromyographic recordings evidenced an earlier and more dramatic muscle denervation in treated SOD1G93A mice that correlated with a decrease in motor neuron survival. Both compounds anticipated disease onset and shortened survival time.

Conclusion and implications: 2BAct and PRXS571 anticipate disease onset, aggravating muscle denervation and motor neuronal death of SOD1G93A mice. This study reveals that the ISR works as a neuroprotective pathway in ALS motor neurons and reveals the toxicity that eIF2B activators may display in ALS patients.

Keywords

amyotrophic lateral sclerosis; electromyography; integrated stress response; motor neuron survival; translational regulation.

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