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

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 strains 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 strains. 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 ALS.

The Role of Mitochondrial Dysfunction and ER Stress in TDP-43 and C9ORF72 ALS

“…Inhibition of eIF2α phosphatase reduced the phenotypes in TDP-43 mutant animal models (Vaccaro et al, 2013 ). However, neither genetic inhibition of the UPR via ablation of PERK, nor genetic UPR enhancement via ablation of GADD34, had a beneficial effect in mutant SOD1 mice (Dzhashiashvili et al, 2019 ). More recent studies in SOD1-iPSC and mouse models demonstrated that MNs are more sensitive to ER stress and identified a number of modifiers, including TUDCA, a bile acid derivative which is currently undergoing clinical trials in ALS (Thams et al, 2019 ; Paganoni et al, 2020 ).…”

PERK Pathway and Neurodegenerative Disease: To Inhibit or to Activate?

“…In the latter mechanism, a problem of topology arises, similar to that mentioned above with α-synuclein, as it is unclear how cytosolic SOD1 is translocated into the ER lumen. It was reported that PERK haploinsufficiency has a deleterious effect on mSOD1 model mice [95], but these results were challenged in a recent study, which showed no significant effects in disease progression [96].…”

Endoplasmic Reticulum Stress and Unfolded Protein Response in Neurodegenerative Diseases

“…Initial studies indicated that Perk haploinsufficiency accelerates experimental ALS in Sod1 transgenic mice, these mice had a reduced capacity to turn down synthesis of misfolded SOD1, leading to an early overload of the UPR [ 123 ]. Furthermore, the genetic ablation of GADD34 [ 124 ] and the inhibition of eIF2α phosphatase [ 125 ] delayed the disease onset and prolonged motor neuron survival. However, more recent studies performed on SOD1 mice showed that neither PERK haploinsufficiency, nor genetic UPR enhancement via ablation of GADD34, is beneficial for mutant SOD1 -induced motor neuron disease [ 126 ].…”