Dysregulation of the unfolded protein response (UPR) in the dorsolateral prefrontal cortex in elderly patients with schizophrenia

Abstract

Abnormalities in protein localization, function, and post-translational modifications (PTMs) are targets of schizophrenia (SCZ) research. As a major contributor to the synthesis, folding, trafficking, and modification of proteins, the endoplasmic reticulum (ER) is well-positioned to sense cellular stress. The unfolded protein response (UPR) is an evolutionarily conserved adaptive reaction to environmental and pathological perturbation in ER function. The UPR is a highly orchestrated and complex cellular response which is mediated through the ER chaperone protein, BiP, three known ER transmembrane stress sensors, protein kinase RNA-like ER kinase (PERK), activating transcription factor-6 (ATF6), inositol requiring enzyme 1α (IRE1α), and their downstream effectors. In this study, we measured protein expression and phosphorylation states of UPR sensor pathway proteins in the dorsolateral prefrontal cortex (DLPFC) of 22 matched pairs of elderly SCZ and comparison subjects. We observed increased protein expression of BiP, decreased PERK, and decreased phosphorylation of IRE1α. We also observed decreased p-JNK2 and increased sXBP1, downstream targets of the IRE1α arm of the UPR. The disconnect between decreased p-IRE1α and increased sXBP1 protein expression led us to measure sXbp1 mRNA. We observed increased expression of the ratio of sXbp1/uXbp1 transcripts , suggesting that splicing of Xbp1 mRNA by IRE1α is increased and drives upregulation of sXBP1 protein expression. These findings suggest an abnormal pattern of UPR activity in SCZ, with specific dysregulation of the IRE1α arm. Dysfunction of this system may lead to abnormal responses to cellular stressors and contribute to protein processing abnormalities previously observed in SCZ.

Chromosome 22q11.2 deletion causes PERK-dependent vulnerability in dopaminergic neurons

“… [57] In addition, PERK expression is reduced in the postmortem brains of schizophrenia patients. [ 51 , 58 ] Here, we suggest that PERK is one of the key factors for understanding the 22q11.2DS-related pathology in dopaminergic neurons and may represent a candidate target for the development of therapeutic and preventive strategies for future diseases in dopaminergic neurons.…”

Cell-type-specific disruption of PERK-eIF2α signaling in dopaminergic neurons alters motor and cognitive function

“…The upregulation of PERK-dependent UPR markers has emerged as a consistent feature of multiple neuropsychiatric disorders, with particular focus on neurodegenerative diseases over the last decade 15 , 17 , 19 – 21 . Evidence of dysregulated PERK-eIF2α signaling in post-mortem brain tissues of PD and AD patients 28 , as well as in preclinical models 70 , 71 of neurodegenerative disease, marked a turning point in the recent research strategy on neurodegenerative disorders, bringing into focus the therapeutic value of UPR modulation across the spectrum of these diseases.…”

“…Moreover, constitutive activity of the UPR is required in cells with a high secretory load, such as neurons, which leads to increased sensitivity of the brain to abnormalities in the UPR, as well as the duration of its activation 14 . This is reflected in studies of neurodegenerative diseases and psychiatric disorders 15 – 18 , including major depressive disorder (MDD) 19 , 20 , and schizophrenia (SCZ) 21 .…”

Aggregative trans-eQTL analysis detects trait-specific target gene sets in whole blood

“…For example, among the enriched gene ontology (GO) terms, GO-0034976: response to endoplasmic reticulum stress 37 (FDR adjusted p-value=0.013), GO-055065 metal ion homeostasis 38 (adjusted p-value=0.029), GO-0006915: apoptotic process 39 (adjusted p-value = 0.029), GO-0043005: neuron projection (adjusted p-value = 0.021) have previously been suggested to be linked to SCZ. Four hallmark gene-sets are also found to be significantly enriched for the selected genes including glycolysis 40 , hypoxia 41 , mTORC1 signaling 42 and unfolded protein response 43 , all of which have suggestive evidence of being associated to SCZ. Using numerous TF databases 44,45 , we found that the selected target genes were enriched (adjusted p-value < 0.05) for targets of 10 TFs (Supplementary Table 4), several of which have been previously reported to be associated with neuropsychiatric disorders 46,47 .…”