Browsing by Subject "UPR"

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    Activation of the XBP1s/O-GlcNAcylation Pathway Improves Functional Outcome After Cardiac Arrest and Resuscitation in Young and Aged Mice.
    (Shock (Augusta, Ga.), 2021-11) Li, Ran; Shen, Yuntian; Li, Xuan; Lu, Liping; Wang, Zhuoran; Sheng, Huaxin; Hoffmann, Ulrike; Yang, Wei

    Abstract

    After cardiac arrest (CA) and resuscitation, the unfolded protein response (UPR) is activated in various organs including the brain. However, the role of the UPR in CA outcome remains largely unknown. One UPR branch involves spliced X-box-binding protein-1 (XBP1s). Notably, XBP1s, a transcriptional factor, can upregulate expression of specific enzymes related to glucose metabolism, and subsequently boost O-linked β-N-acetylglucosamine modification (O-GlcNAcylation). The current study is focused on effects of the XBP1 UPR branch and its downstream O-GlcNAcylation on CA outcome. Using both loss-of-function and gain-of-function mouse genetic tools, we provide the first evidence that activation of the XBP1 UPR branch in the post-CA brain is neuroprotective. Specifically, neuron-specific Xbp1 knockout mice had worse CA outcome, while mice with neuron-specific expression of Xbp1s in the brain had better CA outcome. Since it has been shown that the protective role of the XBP1s signaling pathway under ischemic conditions is mediated by increasing O-GlcNAcylation, we then treated young mice with glucosamine, and found that functional deficits were mitigated on day 3 post CA. Finally, after confirming that glucosamine can boost O-GlcNAcylation in the aged brain, we subjected aged mice to 8 min CA, and then treated them with glucosamine. We found that glucosamine-treated aged mice performed significantly better in behavioral tests. Together, our data indicate that the XBP1s/O-GlcNAc pathway is a promising target for CA therapy.
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    Increasing O-GlcNAcylation is neuroprotective in young and aged brains after ischemic stroke.
    (Experimental neurology, 2021-05) Wang, Zhuoran; Li, Xuan; Spasojevic, Ivan; Lu, Liping; Shen, Yuntian; Qu, Xingguang; Hoffmann, Ulrike; Warner, David S; Paschen, Wulf; Sheng, Huaxin; Yang, Wei
    Spliced X-box binding protein-1 (XBP1s) together with the hexosamine biosynthetic pathway (HBP) and O-GlcNAcylation forms the XBP1s/HBP/O-GlcNAc axis. Our previous studies have provided evidence that activation of this axis is neuroprotective after ischemic stroke and critically, ischemia-induced O-GlcNAcylation is impaired in the aged brain. However, the XBP1s' neuroprotective role and its link to O-GlcNAcylation in stroke, as well as the therapeutic potential of targeting this axis in stroke, have not been well established. Moreover, the mechanisms underlying this age-related impairment of O-GlcNAcylation induction after brain ischemia remain completely unknown. In this study, using transient ischemic stroke models, we first demonstrated that neuron-specific overexpression of Xbp1s improved outcome, and pharmacologically boosting O-GlcNAcylation with thiamet-G reversed worse outcome observed in neuron-specific Xbp1 knockout mice. We further showed that thiamet-G treatment improved long-term functional recovery in both young and aged animals after transient ischemic stroke. Mechanistically, using an analytic approach developed here, we discovered that availability of UDP-GlcNAc was compromised in the aged brain, which may constitute a novel mechanism responsible for the impaired O-GlcNAcylation activation in the aged brain after ischemia. Finally, based on this new mechanistic finding, we evaluated and confirmed the therapeutic effects of glucosamine treatment in young and aged animals using both transient and permanent stroke models. Our data together support that increasing O-GlcNAcylation is a promising strategy in stroke therapy.
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    Olfactory receptor accessory proteins play crucial roles in receptor function and gene choice
    (2017) Sharma, Ruchira

    Understanding how we detect our environment is crucial to understanding how life evolved and now functions. Volatile chemicals from our surroundings are sensed by our olfactory system, a primitive sense that organisms have relied on for survival for millions of years. Mammals express a large family of odorant receptor (OR) genes in the sensory neurons in the nose that mediate this chemosensation. Each mature olfactory sensory neuron (OSN) expresses a single allele of a single OR gene at one time although in the absence of a functional gene OSNs can switch to another OR gene. A functional OR can inhibit the expression of another OR by co-opting the unfolded protein response (UPR). How OSNs make their initial OR gene choice and the mechanisms by which the ORs interact with UPR factors remain unknown.

    In this study, I make use of a double knock out mouse that has RTP1 and RTP2, proteins required for the efficient surface trafficking of ORs in heterologous cells, to study the gene regulation of ORs during a large-scale perturbation of the trafficking of ORs to the cell surface. We initially generate and validate the RTP1 and RTP2 double knock out mouse (RTP1,2DKO) and show that consistent with our heterologous expression system, the mutant mice have OR trafficking defects. These OR trafficking defects give rise to higher rates of cell death and the mutant mice have fewer mature OSNs. Surprisingly we identified a subset of ORs that were overrepresented in the RTP1,2DKO animals. Some of these ORs can target the cell surface in the absence of the RTPs. This finding gave rise to two cohorts of ORs, those that are underrepresented in the mutants and presumably dependent on the RTPs for cell surface trafficking and ORs that are overrepresented in RTP1,2DKO. We show that OSNs expressing underrepresented receptors were more likely to be unable to terminate UPR had a higher tendency to switch the OR it was expressing. Using these two cohorts we showed that the trafficking of ORs to the cell surface is a crucial step in the stabilization of the expression of the OR. In the absence of this cell surface trafficking the OSN is unable to terminate the UPR pathway and either undergoes cell death or OR gene switching.