O-linked β-N-acetylglucosamine modification of proteins is activated in post-ischemic brains of young but not aged mice: Implications for impaired functional recovery from ischemic stress

Liu, Shuai; Sheng, Huaxin; Zhang, Yu; Paschen, Wulf; Yang, Wei

doi:10.1177/0271678x15608393

Cited by 47 publications

(51 citation statements)

References 16 publications

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“…Global SUMOylation, particularly SUMO2/3 conjugation, and ubiquitination were significantly increased in the brain after CA/CPR (Figure 3B), similar to our previous findings using a forebrain ischemia model 7. In contrast to SUMOylation, ubiquitination did not decrease, even at 24 hours’ reperfusion (Figure 3B).…”

Section: Resultssupporting

confidence: 89%

“…Notably, GRP78, a major component of the activating transcription factor 6 UPR branch, was not increased in aged brains, but was increased ≈2‐fold in young brains (Figure 6B). In a previous study, we found that activation of O‐GlcNAcylation is severely impaired in aged compared with young brains at 1 hour reperfusion after forebrain ischemia 7. Herein, this impairment was still evident at 3 hours’ reperfusion after CA/CPR (Figure 6C).…”

Section: Resultsmentioning

confidence: 57%

“…We previously reported that activation of O‐GlcNAcylation is impaired in the aged brain in both ischemic stroke and forebrain ischemia models, a finding that is thought to have important implications in understanding worse outcome in aged brain after ischemia 7, 8. Therefore, we decided to systematically compare activation of proteostasis‐related pathways in young versus aged mice.…”

Section: Resultsmentioning

confidence: 99%

“…Using quantitative reverse transcription–polymerase chain reaction (PCR), levels in mRNAs were analyzed, as described 7. In short, total RNA was extracted from brain cortex and kidney samples using TRIzol reagent (Invitrogen), and used to generate cDNA samples.…”

Section: Methodsmentioning

confidence: 99%

“…Tissue samples were processed for Western blotting using our standard method, as described 7. Briefly, tissue samples (brain cortex, spinal cord, and kidney) were dissected on ice and snap frozen in liquid nitrogen as quickly as possible to prevent deconjugation of SUMOylated and ubiquitinated proteins.…”

Section: Methodsmentioning

confidence: 99%

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Aging Is Associated With Impaired Activation of Protein Homeostasis‐Related Pathways After Cardiac Arrest in Mice

Shen

Yan

Zhao

et al. 2018

JAHA

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BackgroundThe mechanisms underlying worse outcome at advanced age after cardiac arrest (CA) and resuscitation are not well understood. Because protein homeostasis (proteostasis) is essential for cellular and organismal health, but is impaired after CA, we investigated the effects of age on proteostasis‐related prosurvival pathways activated after CA.Methods and ResultsYoung (2–3 months old) and aged (21–22 months old) male C57Bl/6 mice were subjected to CA and cardiopulmonary resuscitation (CPR). Functional outcome and organ damage were evaluated by assessing neurologic deficits, histological features, and creatinine level. CA/CPR‐related changes in small ubiquitin‐like modifier conjugation, ubiquitination, and the unfolded protein response were analyzed by measuring mRNA and protein levels in the brain, kidney, and spinal cord. Thiamet‐G was used to increase O‐linked β‐N‐acetylglucosamine modification. After CA/CPR, aged mice had trended lower survival rates, more severe tissue damage in the brain and kidney, and poorer recovery of neurologic function compared with young mice. Furthermore, small ubiquitin‐like modifier conjugation, ubiquitination, unfolded protein response, and O‐linked β‐N‐acetylglucosamine modification were activated after CA/CPR in young mice, but their activation was impaired in aged mice. Finally, pharmacologically increasing O‐linked β‐N‐acetylglucosamine modification after CA improved outcome.ConclusionsResults suggest that impaired activation of prosurvival pathways contributes to worse outcome after CA/CPR in aged mice because restoration of proteostasis is critical to the survival of cells stressed by ischemia. Therefore, a pharmacologic intervention that targets aging‐related impairment of proteostasis‐related pathways after CA/CPR may represent a promising therapeutic strategy.

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 57%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Aging Is Associated With Impaired Activation of Protein Homeostasis‐Related Pathways After Cardiac Arrest in Mice

Shen

Yan

Zhao

et al. 2018

JAHA

Self Cite

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The emerging link between O-GlcNAcylation and neurological disorders

et al. 2017

Cell. Mol. Life Sci.

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O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is involved in the regulation of many cellular cascades and neurological diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and stroke. In the brain, the expression of O-GlcNAcylation is notably heightened, as is that of O-linked N-acetylglucosaminyltransferase (OGT) and β-N-acetylglucosaminidase (OGA), the presence of which is prominent in many regions of neurological importance. Most importantly, O-GlcNAcylation is believed to contribute to the normal functioning of neurons; conversely, its dysregulation participates in the pathogenesis of neurological disorders. In neurodegenerative diseases, O-GlcNAcylation of the brain's key proteins, such as tau and amyloid-β, interacts with their phosphorylation, thereby triggering the formation of neurofibrillary tangles and amyloid plaques. An increase of O-GlcNAcylation by pharmacological intervention prevents neuronal loss. Additionally, O-GlcNAcylation is stress sensitive, and its elevation is cytoprotective. Increased O-GlcNAcylation ameliorated brain damage in victims of both trauma-hemorrhage and stroke. In this review, we summarize the current understanding of O-GlcNAcylation's physiological and pathological roles in the nervous system and provide a foundation for development of a therapeutic strategy for neurological disorders.

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O-GlcNAc cycling in the developing, adult and geriatric brain

Lagerlöf

2018

J Bioenerg Biomembr

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Hundreds of proteins in the nervous system are modified by the monosaccharide O-GlcNAc. A single protein is often O-GlcNAcylated on several amino acids and the modification of a single site can play a crucial role for the function of the protein. Despite its complexity, only two enzymes add and remove O-GlcNAc from proteins, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Global and local regulation of these enzymes make it possible for O-GlcNAc to coordinate multiple cellular functions at the same time as regulating specific pathways independently from each other. If O-GlcNAcylation is disrupted, metabolic disorder or intellectual disability may ensue, depending on what neurons are affected. O-GlcNAc's promise as a clinical target for developing drugs against neurodegenerative diseases has been recognized for many years. Recent literature puts O-GlcNAc in the forefront among mechanisms that can help us better understand how neuronal circuits integrate diverse incoming stimuli such as fluctuations in nutrient supply, metabolic hormones, neuronal activity and cellular stress. Here the functions of O-GlcNAc in the nervous system are reviewed.

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O-linked β-N-acetylglucosamine modification of proteins is activated in post-ischemic brains of young but not aged mice: Implications for impaired functional recovery from ischemic stress

Cited by 47 publications

References 16 publications

Aging Is Associated With Impaired Activation of Protein Homeostasis‐Related Pathways After Cardiac Arrest in Mice

Aging Is Associated With Impaired Activation of Protein Homeostasis‐Related Pathways After Cardiac Arrest in Mice

The emerging link between O-GlcNAcylation and neurological disorders

O-GlcNAc cycling in the developing, adult and geriatric brain

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