ArticleNeurobiology of disease2019
The UPR-PERK pathway is not a promising therapeutic target for mutant SOD1-induced ALS.
Article in Neurobiology of disease, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 37 citations in OpenAlex.
- Amyotrophic Lateral Sclerosis: Focus on Cytoplasmic Trafficking and Proteostasis.Molecular neurobiology · 2025Review
- Role of lipocalin-2 in amyotrophic lateral sclerosis.Frontiers in aging neuroscience · 2025Review
- GCN2 inhibition reduces mutant SOD1 clustering and toxicity and delays disease progression in an amyotrophic lateral sclerosis mouse model.Translational neurodegeneration · 2024Article
- Article
- PERK modulation, with GSK2606414, Sephin1 or salubrinal, failed to produce therapeutic benefits in the SOD1G93A mouse model of ALS.PloS one · 2024Article
- Dual roles of UPRJournal of molecular medicine (Berlin, Germany) · 2023Review
- Repaglinide Induces ATF6 Processing and Neuroprotection in Transgenic SOD1G93A Mice.International journal of molecular sciences · 2023Article
- The PERK pathway: beneficial or detrimental for neurodegenerative diseases and tumor growth and cancer.Human molecular genetics · 2023Review
- Early activation of cellular stress and death pathways caused by cytoplasmic TDP-43 in the rNLS8 mouse model of ALS and FTD.Molecular psychiatry · 2023Article
- Induction of ER stress-mediated apoptosis through SOD1 upregulation by deficiency of CHI3L1 inhibits lung metastasis.Theranostics · 2023Article
- The Role and Therapeutic Potential of the Integrated Stress Response in Amyotrophic Lateral Sclerosis.International journal of molecular sciences · 2022Review
- Ferroptosis mediates selective motor neuron death in amyotrophic lateral sclerosis.Cell death and differentiation · 2022Article
- α-Amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor and RNA processing gene dysregulation are early determinants of selective motor neuron vulnerability in a mouse model of amyotrophic lateral sclerosis.Brain communications · 2022Article
- The Unfolded Protein Responses in Health, Aging, and Neurodegeneration: Recent Advances and Future Considerations.Frontiers in molecular neuroscience · 2022Review
- Review
- PERK Pathway and Neurodegenerative Disease: To Inhibit or to Activate?Biomolecules · 2021Review
- The Role of Mitochondrial Dysfunction and ER Stress in TDP-43 and C9ORF72 ALS.Frontiers in cellular neuroscience · 2021Review
- Disruption of Endoplasmic Reticulum Proteostasis in Age-Related Nervous System Disorders.Progress in molecular and subcellular biology · 2021Article
- Endoplasmic Reticulum Stress and Unfolded Protein Response in Neurodegenerative Diseases.International journal of molecular sciences · 2020Review
- Fine tuning of the unfolded protein response by ISRIB improves neuronal survival in a model of amyotrophic lateral sclerosis.Cell death & disease · 2020Article
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5 authors at 1 institution in 1 country.
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Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, characterized by motor neuron death in the brain and spinal cord. Mutations in the Cu/Zn superoxide dismutase (SOD1) gene account for ~20% of all familial ALS forms, corresponding to 1%-2% of all ALS cases. One of the suggested mechanisms by which mutant SOD1 (mtSOD1) exerts its toxic effects involves intracellular accumulation of abnormal mtSOD1 aggregates, which trigger endoplasmic reticulum (ER) stress and activate its adaptive signal transduction pathways, including the unfolded protein response (UPR). PERK, an eIF2α kinase, is central to the UPR and is the most rapidly activated pathway in response to ER stress. Previous reports using mtSOD1 transgenic mice indicated that genetic or pharmacological enhancement of the UPR-PERK pathway may be effective in treating ALS. We investigated the response to PERK haploinsufficiency, and the response to deficiency of its downstream effectors GADD34 and CHOP, in five distinct lines of mtSOD1 mice. We demonstrate that, in contrast to a previously published study, PERK haploinsufficiency has no effect on disease in all mtSOD1 lines examined. We also show that deficiency of GADD34, which enhances the UPR by prolonging the phosphorylation of eIF2α, does not ameliorate disease in these mtSOD1 mouse lines. Finally, we demonstrate that genetic ablation of CHOP transcription factor, which is known to be pro-apoptotic, does not ameliorate disease in mtSOD1 mice. Cumulatively, our studies reveal that neither genetic inhibition of the UPR via ablation of PERK, nor genetic UPR enhancement via ablation of GADD34, is beneficial for mtSOD1-induced motor neuron disease. Therefore, the PERK pathway is not a likely target for therapeutic intervention in mtSOD1-induced ALS.
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