The UPR-PERK pathway is not a promising therapeutic target for mutant SOD1-induced ALS

Yulia Dzhashiashvili, Chase P. Monckton, Harini S. Shah, Rejani B. Kunjamma, Brian Popko*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)527-544
Number of pages18
JournalNeurobiology of Disease
StatePublished - Jul 2019


  • Amyotrophic lateral sclerosis
  • CHOP
  • Endoplasmic reticulum stress
  • GADD34
  • Motor neurons
  • PERK
  • SOD1 mice
  • Unfolded protein response

ASJC Scopus subject areas

  • Neurology


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