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

2023; Wiley; Volume: 181; Issue: 3 Linguagem: Inglês

10.1111/bph.16260

1476-5381

Elías Marlin, Miguel Valencia, Nuria Peregrín, Roberto Ferrero, María Jesús Nicolás, Rodrigo Vinueza‐Gavilanes, Antonio Pineda‐Lucena, Julio Artieda, Montserrat Arrasate, Tomás Aragón,

Parkinson's Disease Mechanisms and Treatments

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 SOD1