Abstract
Staufen-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 and its knockdown is protective in models of several neurodegenerative diseases. 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 neurodegenerative diseases and often 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 endoplasmic reticulum (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 individuals with SCA2 or with ALS-causing TDP-43 and C9ORF72 mutations, we found highly increased STAU1 and CHOP levels in basal conditions, and STAU1 knockdown restored CHOP levels to normal. Taken together, these results show that STAU1 overabundance reduces cellular resistance to ER stress and precipitates apoptosis.
Highlights
Stress granules (SGs) are cytoplasmic aggregates of ribosome units, mRNA and RNA-binding proteins that assemble as an adaptive response to stress, allowing survival under adverse conditions
In order to study functional consequences of STAU1 overabundance caused by endoplasmic reticulum (ER) stress in neurological disease, we examined the response of mouse primary cortical neurons and skin fibroblasts derived from WT, or Stau1−/− mice to thapsigargin
We found that STAU1 knockdown attenuated the unfolded protein response (UPR) and apoptotosis (Supplementary Fig. 1a, b), indicating STAU1 has a role modulating life and death decisions when cells are faced with ER stress
Summary
Stress granules (SGs) are cytoplasmic aggregates of ribosome units, mRNA and RNA-binding proteins that assemble as an adaptive response to stress, allowing survival under adverse conditions. Staufen-1 (STAU1) is an RNAbinding protein that localizes to SGs during stress, and can shape a cell’s transcriptome through multiple mechanisms, including regulation of translation efficiency, SG assembly, mRNA transport, and Staufen-mediated mRNA decay. We recently identified STAU1 as an interactor of wild-type and mutant ATXN2. We subsequently discovered substantial increases in STAU1 in multiple cell and animal models of human neurodegenerative diseases, including those carrying mutations in presenilin, microtubule-associated protein tau, huntingtin, TAR DNA-binding protein-43 gene (TARDBP), or C9orf72–SMCR8 complex subunit (C9orf72) [1], as well as stroke and myotonic dystrophy [1, 3, 12]. Autophagy defects and IRES-mediated translation are the currently described mechanisms for STAU1 increase, both relevant protein abundance regulatory pathways during neurodegeneration [1, 13]
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