During the adaptive UPR, XBP1s induces expression of ER chaperones and co-factors, ER-associated protein degradation (ERAD) components and lipid biosynthesis to increase the protein folding and quality control capacity (Walter and Ron, 2011). of mutations suggest common pathogenic mechanisms in fALS and sALS (Neumann et al., 2006; Bosco et al., 2010; Farg et al., 2012). The development of genetic models of ALS has enabled dissection of disease course at histological, cellular and molecular levels (Philips and Rothstein, 2015). Although multiple mechanisms are proposed to drive ALS (Taylor et al., 2016), several recent unbiased studies in mutant SOD1 transgenic mice and induced pluripotent stem cell (iPSC)-derived patient motoneurons have identified endoplasmic reticulum (ER) stress as an early and transversal pathogenic mechanism underlying selective vulnerability of motoneurons in ALS (Saxena et al., 2009; Kiskinis et al., 2014; Filzac de LEtang et al., 2015; Sun et al., 2015). ER stress is a condition generated by abnormal levels of misfolded proteins in the ER lumen, engaging a signal transduction pathway termed the unfolded protein response (UPR). The UPR operates as a central controller of cell fate, mediating initial adaptive responses to restore proteostasis through various mechanisms including transcriptional and translational regulation, enhancement of protein quality control mechanisms, degradation of abnormal proteins, among other outputs (Hetz, 2012). The UPR is a binary pathway that shifts its signaling toward a terminal phase to eliminate irreversibly damaged cells through apoptosis (Walter and Ron, 2011). The adaptive UPR is marked by rapid inhibition of protein translation due to the phosphorylation of the eukaryotic initiation factor 2 (eIF2), in addition to transcriptional induction of chaperones, foldases, protein quality control and degradation systems, lipid biosynthesis, among others. Under pathological conditions of chronic ER stress as observed in numerous neurodegenerative diseases (Hetz and Mollereau, 2014; Scheper and Hoozemans, 2015; Smith and Mallucci, Rabbit Polyclonal to KLF 2016), the terminal UPR engages pro-inflammatory and apoptotic cascades leading to cell death (Urra et al., 2013; Oakes and Papa, 2015). UPR Signaling Pathways The UPR transduces information about protein folding status from ER lumen to cytosol and nucleus through the action of various type-I ER transmembrane proteins that respond to the accumulation of misfolded proteins. These sensors reprogram the transcriptional and translational profile of the cell by a concerted action of transcription factors, phosphorylation events and RNA processing (Hetz et al., 2015). The mammalian UPR relies on three stress transducers, named activating transcription factor 6 (ATF6), protein kinase R (PKR)-like ER kinase (PERK) and inositol-requiring enzyme 1 (IRE1), being IRE1 the most conserved sensor from yeast to human (Wang and Kaufman, 2016). IRE1 is a kinase and endoribonuclease that upon ER stress is activated by dimerization and auto-transphosphorylation to catalyze the unconventional splicing of X-box binding protein 1 (XBP1) mRNA (Figure ?(Figure1),1), thus leading to production of a potent transcription factor termed XBP1s (Hetz et MRS1706 al., 2015). During the adaptive UPR, XBP1s induces expression of ER chaperones and co-factors, ER-associated protein degradation (ERAD) components and lipid biosynthesis to increase the protein folding and quality control capacity (Walter and Ron, 2011). When ER stress is chronic, IRE1 is overactivated through assembly into high-order oligomers and reduces its substrate specificity to catalyze degradation of mRNA and microRNAs (Figure ?(Figure1),1), an activity termed Regulated IRE1-dependent Decay (RIDD; Maurel et al., 2014). The activation of RIDD depletes ER components and reflects the terminal UPR directing cell fate towards apoptosis by directly MRS1706 controlling the stability of microRNAs, apoptosis genes and pro-inflammatory factors (Hollien and Weissman, 2006; Han et al., 2009; Hollien et al., 2009; Lerner et al., 2012; Ghosh et al., 2014). Furthermore, MRS1706 IRE1 can interact with cytosolic components, including adaptor proteins, to fine-tune UPR outputs in a dynamic fashion (Figure ?(Figure1),1), comprising a protein platform termed UPRosome (Hetz and Glimcher, 2009). For instance, IRE1 can be coupled to.