Age-Related Memory Impairment and Sex-Specific Alterations in Phosphorylation of the Rpt6 Proteasome Subunit and Polyubiquitination in the Basolateral Amygdala and Medial Prefrontal Cortex

Dulka, Brooke N.; Trask, Sydney; Helmstetter, Fred J.

doi:10.3389/fnagi.2021.656944

Cited by 19 publications

(21 citation statements)

References 42 publications

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“…These findings indicate that males and females may differ in the functional role of ubiquitin-proteasome activity during fear memory formation, though this has never been tested. Furthermore, males and females differ in the age-related engagement of the protein degradation process following fear memory retrieval (Dulka et al, 2021 ), further emphasizing the importance of sex in studying UPS function during fear memory formation and disease-associated memory loss.…”

Section: Introductionmentioning

confidence: 99%

Proteomic Analysis Reveals Sex-Specific Protein Degradation Targets in the Amygdala During Fear Memory Formation

Farrell

Musaus

Navabpour

et al. 2021

Front. Mol. Neurosci.

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Ubiquitin-proteasome mediated protein degradation has been widely implicated in fear memory formation in the amygdala. However, to date, the protein targets of the proteasome remain largely unknown, limiting our understanding of the functional significance for protein degradation in fear memory formation. Additionally, whether similar proteins are targeted by the proteasome between sexes has yet to be explored. Here, we combined a degradation-specific K48 Tandem Ubiquitin Binding Entity (TUBE) with liquid chromatography mass spectrometry (LC/MS) to identify the target substrates of the protein degradation process in the amygdala of male and female rats following contextual fear conditioning. We found that males (43) and females (77) differed in the total number of proteins that had significant changes in K48 polyubiquitin targeting in the amygdala following fear conditioning. Many of the identified proteins (106) had significantly reduced levels in the K48-purified samples 1 h after fear conditioning, suggesting active degradation of the substrate due to learning. Interestingly, only 3 proteins overlapped between sexes, suggesting that targets of the protein degradation process may be sex-specific. In females, many proteins with altered abundance in the K48-purified samples were involved in vesicle transport or are associated with microtubules. Conversely, in males, proteins involved in the cytoskeleton, ATP synthesis and cell signaling were found to have significantly altered abundance. Only 1 protein had an opposite directional change in abundance between sexes, LENG1, which was significantly enhanced in males while lower in females. This suggests a more rapid degradation of this protein in females during fear memory formation. Interestingly, GFAP, a critical component of astrocyte structure, was a target of K48 polyubiquitination in both males and females, indicating that protein degradation is likely occurring in astrocytes following fear conditioning. Western blot assays revealed reduced levels of these target substrates following fear conditioning in both sexes, confirming that the K48 polyubiquitin was targeting these proteins for degradation. Collectively, this study provides strong evidence that sex differences exist in the protein targets of the degradation process in the amygdala following fear conditioning and critical information regarding how ubiquitin-proteasome mediated protein degradation may contribute to fear memory formation in the brain.

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Section: Introductionmentioning

confidence: 99%

Proteomic Analysis Reveals Sex-Specific Protein Degradation Targets in the Amygdala During Fear Memory Formation

Farrell

Musaus

Navabpour

et al. 2021

Front. Mol. Neurosci.

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“…Furthermore, we found that in the amygdala and dorsal hippocampus male and female rats differed in how the proteasome could be regulated by protein kinase A (PKA) and calcium/calmodulin-dependent protein kinase II (CaMKII) following learning ( Devulapalli et al 2019 ). Additionally, recent evidence suggests sex differences in how protein degradation is engaged following memory retrieval in aged animals ( Dulka et al 2021 ). However, to date, these remain the only studies that have directly compared the protein degradation process in male and female rodents following behavioral training or retrieval.…”

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confidence: 99%

Females, but not males, require protein degradation in the hippocampus for contextual fear memory formation

et al. 2021

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Strong evidence supports a role for protein degradation in fear memory formation. However, these data have been largely done in only male animals. Here, we found that following contextual fear conditioning, females, but not males, had increased levels of proteasome activity and K48 polyubiquitin protein targeting in the dorsal hippocampus, the latter of which occurred at chaperones or RNA processing proteins. In vivo CRISPR–dCas9-mediated repression of protein degradation in the dorsal hippocampus impaired contextual fear memory in females, but not males. These results suggest a sex-specific role for protein degradation in the hippocampus during the consolidation of a contextual fear memory.

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“…The significant difference between young and aging mice under control conditions ( P = 0.0180, Tukey’s multiple comparisons test) disappeared when the mice were under anesthesia/surgery conditions in a context-related test, although the interaction of anesthesia/surgery and age was not significant [P surg = 0.0025, F surg(1, 30) = 10.90; P age = 0.0005, F age(1, 30) = 15.34; P int = 0.5892, F int(1, 30) = 0.2979] ( Figure 1G ). Analysis results did not show any differences among the four groups in the tone-related test, which requires proper function of the amygdala ( Dulka et al, 2021 ). [P surg = 0.3238, F surg(1, 30) = 1.006; P age = 0.0464, F age(1, 30) = 4.315; P int = 0.1269, F int (1, 30) = 2.465] ( Figure 1H ).…”

Section: Resultsmentioning

confidence: 99%

Characterization of circRNA-Associated-ceRNA Networks Involved in the Pathogenesis of Postoperative Cognitive Dysfunction in Aging Mice

Zhang

Lin

Yang

et al. 2022

Front. Aging Neurosci.

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Postoperative cognitive dysfunction (POCD) is a clinical entity associated with declined cognitive function following surgery. It occurs more frequently in elderly patients. Recent studies have shown that circRNA-associated-ceRNA networks, constructed based on interactions between circRNA-miRNA and miRNA-mRNA, provide key insight into the molecular mechanisms underlying the pathogenesis of several neurological diseases. However, the mechanism of POCD remains undetermined. In this study, laparotomies were performed under isoflurane anesthesia on young (2-month-old) and aging (17-month-old) male C57BL/6 mice. The results showed that the aging mice were more likely than the young mice to develop POCD. Subsequently, differentially expressed circRNAs, miRNAs, and mRNAs were characterized by RNA sequencing the hippocampi of young and aging mice under control and surgery conditions. Six circRNAs, 6 miRNAs, and 203 mRNAs were identified to construct the circRNA-associated-ceRNA network for the control condition, while 13 circRNAs, 8 miRNAs, and 189 mRNAs were used for the circRNA-associated-ceRNA network for the surgery condition. Further Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of these two networks revealed that the circRNA-associated-ceRNA networks are involved in POCD pathogenesis though modulating the Wnt and VEGF signaling pathways, as well as neural processes associated with long-term synaptic depression and synaptic transmission. In particular, the mmu-miR-298-5P regulatory pathway identified in this study’s mouse model suggests that mm9_circ_009789- and mm9_circ_004229-associated-ceRNA networks as closely related to the occurrence of POCD through regulating PKC signaling pathway, neural cell apoptosis and glycolipid metabolism pathway. These findings provide possible insight into the role of the circRNA-associated-ceRNA networks, helping to unravel the complexity of the molecular pathogenesis of POCD.

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Age-Related Memory Impairment and Sex-Specific Alterations in Phosphorylation of the Rpt6 Proteasome Subunit and Polyubiquitination in the Basolateral Amygdala and Medial Prefrontal Cortex

Cited by 19 publications

References 42 publications

Proteomic Analysis Reveals Sex-Specific Protein Degradation Targets in the Amygdala During Fear Memory Formation

Proteomic Analysis Reveals Sex-Specific Protein Degradation Targets in the Amygdala During Fear Memory Formation

Females, but not males, require protein degradation in the hippocampus for contextual fear memory formation

Characterization of circRNA-Associated-ceRNA Networks Involved in the Pathogenesis of Postoperative Cognitive Dysfunction in Aging Mice

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