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A Quick Phenotypic Neurological Scoring System for Evaluating Disease Progression in the SOD1-G93A Mouse Model of ALS
Published on: October 6, 2015
PERK modulation, with GSK2606414, Sephin1 or salubrinal, failed to produce therapeutic benefits in the SOD1G93A mouse
Fernando G Vieira1, Valerie R Tassinari1, Joshua D Kidd1
1ALS Therapy Development Institute, Watertown, MA, United States of America.
Abstract:
Amyotrophic lateral sclerosis (ALS) has been linked to overactivity of the protein kinase RNA-like ER kinase (PERK) branch of the unfolded protein response (UPR) pathway, both in ALS patients and mouse models. However, attempts to pharmacologically modulate PERK for therapeutic benefit have yielded inconsistent and often conflicting results. This study sought to address these discrepancies by comprehensively evaluating three commonly used, CNS-penetrant, PERK modulators (GSK2606414, salubrinal, and Sephin1) in the same experimental models, with the goal of assessing the viability of targeting the PERK pathway as a therapeutic strategy for ALS. To achieve this goal, a tunicamycin-challenge assay was developed using wild-type mice to monitor changes in liver UPR gene expression in response to PERK pathway modulation. Subsequently, multiple dosing regimens of each PERK modulator were tested in standardized, well-powered, gender-matched, and litter-matched survival efficacy studies using the SOD1G93A mouse model of ALS. The alpha-2-adrenergic receptor agonist clonidine was also tested to elucidate the results obtained from the Sephin1, and of the previously reported guanabenz studies, by comparing the effects of presence or absence of α-2 agonism. The results revealed that targeting PERK may not be an ideal approach for ALS treatment. Inhibiting PERK with GSK2606414 or activating it with salubrinal did not confer therapeutic benefits. While Sephin1 showed some promising therapeutic effects, it appears that these outcomes were mediated through PERK-independent mechanisms. Clonidine also produced some favorable therapeutic effects, which were unexpected and not linked to the UPR. In conclusion, this study highlights the challenges of pharmacologically targeting PERK for therapeutic purposes in the SOD1G93A mouse model and suggests that exploring other targets within, and outside, the UPR may be more promising avenues for ALS treatment.
Insights
Targeting the PERK pathway, a component of the unfolded protein response (UPR), shows limited therapeutic potential for amyotrophic lateral sclerosis (ALS). Modulating PERK did not improve survival in ALS mouse models, suggesting alternative therapeutic strategies are needed.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Amyotrophic lateral sclerosis (ALS) is associated with overactive PERK signaling in the unfolded protein response (UPR) pathway.
- Previous therapeutic attempts targeting PERK in ALS have produced conflicting results.
Purpose of the Study:
- To comprehensively evaluate the therapeutic viability of targeting the PERK pathway for ALS.
- To assess three common CNS-penetrant PERK modulators (GSK2606414, salubrinal, Sephin1) in ALS mouse models.
- To investigate the role of alpha-2 adrenergic agonism in Sephin1 and guanabenz efficacy.
Main Methods:
- Developed a tunicamycin-challenge assay in wild-type mice to monitor UPR gene expression.
- Tested multiple dosing regimens of GSK2606414, salubrinal, and Sephin1 in SOD1G93A ALS mouse models.
- Evaluated the alpha-2 adrenergic receptor agonist clonidine for its effects on ALS and UPR.
Main Results:
- PERK inhibition (GSK2606414) or activation (salubrinal) did not improve ALS mouse survival.
- Sephin1 demonstrated therapeutic effects, but these were independent of PERK modulation.
- Clonidine showed unexpected therapeutic benefits unrelated to the UPR.
Conclusions:
- Pharmacologically targeting the PERK pathway presents challenges for ALS treatment in the SOD1G93A mouse model.
- PERK-independent mechanisms may underlie observed effects of some modulators.
- Exploring therapeutic targets beyond the UPR is recommended for ALS.
