Deficiency of the immunoproteasome subunit β5i/LMP7 supports the anxiogenic effects of mild stress and facilitates cued fear memory in mice

Gorny, Xenia; Säring, Paula; Acosta, Jorge R. Bergado; Kahl, Evelyn; Kolodziejczyk, Malgorzata H.; Cammann, Clemens; Wernecke, Kerstin E.A.; Mayer, Dana; Landgraf, Peter; Seifert, Ulrike; Dieterich, Daniela C.; Fendt, Markus

doi:10.1016/j.bbi.2019.02.018

Cited by 6 publications

(5 citation statements)

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“…5A ), in line with a previous study reporting behaviour deficits in such animals. 18 Next, to investigate whether the TKO mice showed any alterations in locomotor activity, 1-year-old TKO mice and age-matched WT mice were subjected to a gait analysis. The generated metrics show a higher variance in the stride length, width and toe spread of TKO animals compared with those of WT mice ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, mice lacking LMP2 or LMP7 display substantial immunological deficiencies that may also contribute to the observed neurological phenotype. Recent studies suggest that both LMP7-deficient mice and LMP2-deficient rats have some neurobehavioural dysfunctions, 18 , 37 which may be even more pronounced in the absence of all three immunoproteasome subunits. Taken together, we conclude that all three immunoproteasome subunits, LMP2, MECL-1 and LMP7, are required in order to effectively protect the ageing brain from neurological disorders.…”

Section: Discussionmentioning

confidence: 99%

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Immunoproteasome deficiency results in age-dependent development of epilepsy

Leister,

Krause,

Gil

et al. 2023

Brain Communications

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The immunoproteasome is a central protease complex required for optimal antigen presentation. Immunoproteasome activity is also associated with facilitating degradation of misfolded and oxidized proteins, which prevents cellular stress. While extensively studied during diseases with increasing evidence suggesting a role for the immunoproteasome during pathological conditions including neurodegenerative diseases, this enzyme complex is believed to be mainly not expressed in the healthy brain. Here, we show an age-dependent increase in polyubiquitination in the brain of wild-type mice, accompanied with induction of immunoproteasomes, which was most prominent in neurons and microglia. In contrast, mice completely lacking immunoproteasomes (triple-knockout mice), displayed a strong increase in polyubiquitinated proteins already in the young brain and developed spontaneous epileptic seizures, beginning at the age of 6 months. Injections of kainic acid led to high epilepsy-related mortality of aged triple-knockout mice, confirming increased pathological hyperexcitability states. Notably, the expression of the immunoproteasome was reduced in the brains of patients suffering from epilepsy. In addition, aged triple-knockout mice showed increased anxiety, tau hyperphosphorylation and degeneration of Purkinje cell population with the resulting ataxic symptoms and locomotion alterations. Collectively, our study suggests a critical role for the immunoproteasome in the maintenance of a healthy brain during aging.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Immunoproteasome deficiency results in age-dependent development of epilepsy

Leister,

Krause,

Gil

et al. 2023

Brain Communications

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show abstract

“…Interestingly, in this study, we provided new evidence that LMP2 gene deletion resulted in cognitive dysfunction, reduced rats’ exploratory activities, increased rats’ anxiety-like behavior and without strong effects on gross locomotor abilities (such as swimming speed). Similarly, a recent reported that LMP7-deficient mice expressed more anxiety and increased cued fear and no strong effects on gross locomotor abilities [ 12 ]. Taken together, these data suggest that the immunoproteasomeis closely related to cognitionand emotional behavior.…”

Section: Discussionmentioning

confidence: 95%

“…More interestingly, recent research confirmed a relationship between immunoproteasome and emotion in animal experiment. Gorny X, et al reported that β5i/LMP7 gene deletion mice displayed more anxiety after mild stress and increased cued fear after fear conditioning compared with the WT mice [ 12 ]. These findings suggest that the basal proper formation of immunoproteasome in healthy mice seem to be involved in the regulation of anxiety and cued fear levels.…”

Section: Introductionmentioning

confidence: 99%

LMP2 deficiency causes abnormal metabolism, oxidative stress, neuroinflammation, myelin loss and neurobehavioral dysfunctions

et al. 2023

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Background Substantial evidence suggests that immunoproteasome is implicated in the various neurological diseases such as stroke, multiple sclerosis and neurodegenerative diseases. However, whether the immunoproteasome itself deficiency causes brain disease is still unclear. Therefore, the aim of this study was to explore the contribution of the immunoproteasome subunit low molecular weight protein 2 (LMP2) in neurobehavioral functions. Methods Male LMP2 gene completed knockout (LMP2-KO) and littermate wild type (WT) Sprague–Dawley (SD) rats aged 12-month-old were used for neurobehavioral testing and detection of proteins expression by western blotting and immunofluorescence. A battery of neurobehavioral test tools including Morris water maze (MWM), open field maze, elevated plus maze were used to evaluate the neurobehavioral changes in rats. Evans blue (EB) assay, Luxol fast blue (LFB) and Dihydroethidium (DHE) staining were applied to explore the blood–brain barrier (BBB) integrity, brain myelin damage and brain intracellular reactive oxygen species (ROS) levels, respectively. Results We firstly found that LMP2 gene deletion did not cause significantly difference in rats’ daily feeding activity, growth and development as well as blood routine, but it led to metabolic abnormalities including higher levels of low-density lipoprotein cholesterol, uric acid and blood glucose in the LMP2-KO rats. Compared with the WT rats, LMP2-KO rats displayed obviously cognitive impairment and decreased exploratory activities, increased anxiety-like behavior and without strong effects on gross locomotor abilities. Furthermore, multiple myelin loss, increased BBB leakage, downregulation of tight junction proteins ZO-1, claudin-5 and occluding, and enhanced amyloid-β protein deposition were observed in brain regions of LMP2-KO rats. In addition, LMP2 deficiency significantly enhanced oxidative stress with elevated levels of ROS, caused the reactivation of astrocytes and microglials and markedly upregulated protein expression levels of interleukin (IL)-1 receptor-associated kinase 1 (IRAK1), IL-6 and tumor necrosis factor-α (TNF-α) compared to the WT rats, respectively. Conclusion These findings highlight LMP2 gene global deletion causes significant neurobehavioral dysfunctions. All these factors including metabolic abnormalities, multiple myelin loss, elevated levels of ROS, increased BBB leakage and enhanced amyloid-β protein deposition maybe work together and eventually led to chronic oxidative stress and neuroinflammation response in the brain regions of LMP2-KO rats, which contributed to the initial and progress of cognitive impairment.

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“…A recent study has shown that ONX0914 treatment prevented the disease exacerbation of experimental autoimmune encephalomyelitis [ 22 ]. Interestingly, β 5i/LMP7-deficient mice expressed more anxiety after mild stress and increased cued fear after fear conditioning [ 41 ], suggesting LMP7 implicated in the pathophysiological mechanism of emotion behavior. Taken together, this evidence supports the hypothesis of the involvement of the immunoproteasome in the pathogenesis of chronic hypoperfusion-induced white matter injury.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Immunoproteasome Subunit LMP7 Ameliorates Cerebral White Matter Demyelination Possibly via TGFβ/Smad Signaling

Chen

Yao

Lin

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Objectives. Chronic cerebral hypoperfusion induces white matter ischemic injury and cognitive impairment, whereas the mechanism remains unclear. Immunoproteasomes have been implicated in the pathogenesis of acute ischemia stroke and multiple sclerosis. However, the expression and role of immunoproteasomes in the brain of chronic cerebral hypoperfusion remain to be clarified. Methods. Chronic white matter ischemic injury mice models were induced by bilateral carotid artery stenosis (BCAS). A selective immunoproteasome subunit low-molecular-mass peptide-7 (LMP7) inhibitor PR957 was administered to mice. Cognitive function, white matter integrity, and potential pathways were assessed after BCAS. Results. The present study found that chronic cerebral hypoperfusion following BCAS induced cerebral white matter demyelination and cognitive impairment, accompanied with elevated expression of the immunoproteasomes LMP2 and LMP7, activation of astrocytes and microglia, and increased production of inflammatory cytokines (e.g., interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-10, transforming growth factor-β1 (TGFβ1), and insulin-like growth factor-1 (IGF-1)). However, inhibition of LMP7 with the specific proteasome inhibitor PR957 significantly mitigated the histological damage of the white matter, suppressed inflammatory response, and paralleled by an improvement of cognitive function. Furthermore, treatment of PR957 significantly upregulated the level of TGFβ1, the total expression level, and the phosphorylation level of Smad2/3 and promoted brain remyelination. Surprisingly, PR957 alone had no effects on the neuroinflammation response and the activation of TGFβ/Smad signaling in the sham-operated (BCAS-nonoperated) mice. Conclusions. The possible mechanism underlying this was attributed to that the immunoproteasome regulates TGFβ/Smad signaling-mediated neuroinflammation and oligodendrocyte remyelination.

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Deficiency of the immunoproteasome subunit β5i/LMP7 supports the anxiogenic effects of mild stress and facilitates cued fear memory in mice

Cited by 6 publications

References 85 publications

Immunoproteasome deficiency results in age-dependent development of epilepsy

Immunoproteasome deficiency results in age-dependent development of epilepsy

LMP2 deficiency causes abnormal metabolism, oxidative stress, neuroinflammation, myelin loss and neurobehavioral dysfunctions

Inhibition of the Immunoproteasome Subunit LMP7 Ameliorates Cerebral White Matter Demyelination Possibly via TGFβ/Smad Signaling

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