AbstractStaufen-1 (STAU1) is an RNA binding protein that becomes highly overabundant in numerous neurodegenerative disease models, including those carrying mutations in presenilin1 (PSEN1), microtubule associated protein tau (MAPT), huntingtin (HTT), TAR DNA-binding protein-43 gene (TARDBP) or C9orf72. We previously reported that elevations in STAU1 determine autophagy defects. Additional functional consequences of STAU1 overabundance, however, have not been investigated. We studied the role of STAU1 in the chronic activation of the Unfolded Protein Response (UPR), a common feature among the neurodegenerative diseases where STAU1 is increased, and is directly associated with neuronal death. Here we report that STAU1 is a novel modulator of the UPR, and is required for apoptosis induced by activation of the PERK-CHOP pathway. STAU1 levels increased in response to multiple ER stressors and exogenous expression of STAU1 was sufficient to cause apoptosis through the PERK-CHOP pathway of the UPR. Cortical neurons and skin fibroblasts derived from Stau1−/− mice showed reduced UPR and apoptosis when challenged with thapsigargin. In fibroblasts from SCA2 patients or with ALS-causing TDP-43 and C9ORF72 mutations we found highly increased STAU1 and CHOP levels in basal conditions. STAU1 knockdown restored CHOP levels to normal. Taken together, these results show STAU1 overabundance reduces cellular resistance to ER stress and precipitates apoptosis.
Spliced X-Box Binding Protein 1 Couples the Unfolded Protein Response to Hexosamine Biosynthetic Pathway
