A novel heat shock protein alpha 8 (Hspa8) molecular network mediating responses to stress- and ethanol-related behaviors

Abstract

Genetic differences mediate individual differences in susceptibility and responses to stress and ethanol, although, the specific molecular pathways that control these responses are not fully understood. Heat shock protein alpha 8 (Hspa8) is a molecular chaperone and member of the heat shock protein family that plays an integral role in the stress response and that has been implicated as an ethanol-responsive gene. Therefore, we assessed its role in mediating responses to stress and ethanol across varying genetic backgrounds. The hippocampus is an important mediator of these responses, and thus, was examined in the BXD family of mice in this study. We conducted bioinformatic analyses to dissect genetic factors modulating Hspa8 expression, identify downstream targets of Hspa8, and examined its role. Hspa8 is trans-regulated by a gene or genes on chromosome 14 and is part of a molecular network that regulates stress- and ethanol-related behaviors. To determine additional components of this network, we identified direct or indirect targets of Hspa8 and show that these genes, as predicted, participate in processes such as protein folding and organic substance metabolic processes. Two phenotypes that map to the Hspa8 locus are anxiety-related and numerous other anxiety- and/or ethanol-related behaviors significantly correlate with Hspa8 expression. To more directly assay this relationship, we examined differences in gene expression following exposure to stress or alcohol and showed treatment-related differential expression of Hspa8 and a subset of the members of its network. Our findings suggest that Hspa8 plays a vital role in genetic differences in responses to stress and ethanol and their interactions.

The Isoquinoline Alkaloid Dauricine Targets Multiple Molecular Pathways to Ameliorate Alzheimer‐Like Pathological Changes In Vitro

“…In addition, we found some common proteins that were differentially expressed among the four comparison groups ( Figure S1A and Tables S1–4 ). These differential proteins included signaling protein high-mobility group protein B1 (HMGB1) a mediator of neurite degeneration through the identification of the pathological signaling pathway in AD [ 13 ]; molecular chaperones (heat shock cognate 71 kDa protein (HSP7C)), a molecular chaperone and a member of the heat shock protein family that plays an integral role in the stress response [ 14 ]; translationally controlled tumor protein (TCTP), which has critical roles in the defense against oxidative and thermal stresses [ 15 ] (shown in Table S1 ); endoplasmic reticulum (ER) stress-associated protein (protein disulfide-isomerase A6 (PDIA6)), a protein related to ER stress that plays a critical role in most biological processes [ 16 ]; oxidative stress-associated protein (D-3-phosphoglycerate dehydrogenase (SERA)), a protein involved in the metabolism and development of the central nervous system [ 17 ]; cytoskeleton-associated protein (peripherin (PERI)), a type III intermediate filament (IF) protein that plays a contributory role in motor neuron disease [ 18 , 19 ]; molecular chaperone (stress-induced-phosphoprotein 1 (STIP1)), a cochaperone intermediating Hsp70/Hsp90 exchange of client proteins and involved in prion protein-mediated neuronal signaling [ 20 ] (shown in Table S2 ); and cytoskeleton-associated protein (TPIS) (shown in Table S3 ). We found that two proteins, namely, isocitrate dehydrogenase [NADP] cytoplasmic (IDHC), which plays important roles in energy and biosynthesis metabolisms [ 21 ], and eukaryotic translation initiation factor 1b (EIF1B), an antiapoptotic protein that protects cells uniquely from Fas-induced apoptosis [ 22 ], were commonly changed in various concentrations of DAU-treated N2a/APP cells compared with the vehicle-treated N2a/APP cells (shown in Figure S1B and Table S8 ).…”

Analyses of differentially expressed genes after exposure to acute stress, acute ethanol, or a combination of both in mice

“…Previous studies have evaluated whether any of the specific phenotypes mapped back to the location of the differentially expressed genes in their respective group (Bice et al, 2010, 2006; Carhuatanta, Shea, Herman, & Jankord, 2014; Cook et al, 2015; Overall et al, 2009; Palmer, Lessov-Schlaggar, Ponder, McKinnon, & Phillips, 2006; Porcu et al, 2011; Urquhart et al, 2016). However, in the present study, only one phenotype mapped back to the location of a gene that was correlated with it: Cnot6l from the RSE vs. NOE group.…”

The effect of alcohol on the differential expression of cluster of differentiation 14 gene, associated pathways, and genetic network

“…One such chronic illness linked to Cd14 and neuroinflammation is Alzheimer’s disease, which is heavily implicated with the hippocampus and can be detected in the hippocampal formation at an early stage before further symptoms arise [18, 19]. Perhaps more importantly, our previous studies have shown that gene expression in the hippocampus is particularly sensitive to the effects of acute ethanol (1.8 g/kg) [20, 21]. Others have also shown that acute ethanol (2.0 g/kg) produces brain region-specific changes in gene expression, including in the hippocampus [22].…”