Abstract
The endoplasmic reticulum (ER) plays an important role in maintenance of proteostasis through the unfolded protein response (UPR), which is strongly activated in most neurodegenerative disorders. UPR signalling pathways mediated by IRE1α and ATF6 play a crucial role in the maintenance of ER homeostasis through the transactivation of an array of transcription factors. When activated, these transcription factors induce the expression of genes involved in protein folding and degradation with pro-survival effects. However, the specific contribution of these transcription factors to different neurodegenerative diseases remains poorly defined. Here, we characterised 44 target genes strongly influenced by XBP1 and ATF6 and quantified the expression of a subset of genes in the human post-mortem spinal cord from amyotrophic lateral sclerosis (ALS) cases and in the frontal and temporal cortex from frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD) cases and controls. We found that IRE1α-XBP1 and ATF6 pathways were strongly activated both in ALS and AD. In ALS, XBP1 and ATF6 activation was confirmed by a substantial increase in the expression of both known and novel target genes involved particularly in co-chaperone activity and ER-associated degradation (ERAD) such as DNAJB9, SEL1L and OS9. In AD cases, a distinct pattern emerged, where targets involved in protein folding were more prominent, such as CANX, PDIA3 and PDIA6. These results reveal that both overlapping and disease-specific patterns of IRE1α-XBP1 and ATF6 target genes are activated in AD and ALS, which may be relevant to the development of new therapeutic strategies.Graphical abstractThe endoplasmic reticulum (ER) plays an important role in maintenance of proteostasis through the unfolded protein response (UPR). Two major UPR signalling pathways are mediated by IRE1α and ATF6. Here, we demonstrate that these pathways activate differential gene sets in human post-mortem tissues derived from amyotrophic lateral sclerosis (ALS) compared to Alzheimer’s disease (AD) cases. Our results identify IRE1α and ATF6 specific targets that can have major implications in the development of new therapeutic strategies and potential biomarkers.
Highlights
The majority of neurodegenerative diseases such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) areL
For each RefSeq sequence of XBP1 target gene, we investigated the presence of endoplasmic reticulum (ER) stress response elements
We selected the candidate genes that are mainly involved in the protein homeostasis process, which were extrapolated from gene ontology (GO) enrichment analysis performed on the genes regulated by the unfolded protein response (UPR) transcription factor (TF)
Summary
The majority of neurodegenerative diseases such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) areL. IRE1α-XBP1 and ATF6 pathways regulate the transcriptional induction of a similar set of genes, which are characterised by the presence of specific cis-acting elements in their promoter regions (Acosta-Alvear et al 2007; Yamamoto et al 2007; Pincus et al 2010; Shoulders et al 2013) These cis-acting elements are recognised by XBP1 and can be divided into four main binding sites: ERSE (ER stress response elements, the consensus sequence of which is CCAAT-N9-CCACG) (Yoshida et al 2001), ERSE-II (ER stress response element II, ATTGG-N1-CCACG), ERSE-26 (CCAAT-N26-CCACG) and UPRE (unfolded protein response element) (Yamamoto et al 2004; Acosta-Alvear et al 2007; Misiewicz et al 2013). Due to this close interaction, the specific contribution of IRE1α-XBP1 and ATF6 pathways in normal and pathological condition is still not well understood
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