Co-translational protein aggregation after transient cerebral ischemia

Liu, C.L.; Ge, Pengfei; Zhang, Fan; Hu, Bingren

doi:10.1016/j.neuroscience.2005.05.015

Cited by 70 publications

(89 citation statements)

References 37 publications

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“…Both HSC70 and HSP70 are components of insoluble aggregates following stress (Liu et al 2005 andZhang et al 2006), and CHIP in similar insoluble aggregates may explain the decreases in CHIP observed in our studies. Liu et al (2005) observed CHIP within protein aggregates during recovery periods of 4 h or greater in CA1 neurons that were destined to die following transient cerebral ischemia. These aggregates were mainly associated with intracellular vesicles and the nuclear membrane.…”

Section: Discussionsupporting

confidence: 74%

Brain distribution of carboxy terminus of Hsc70-interacting protein (CHIP) and its nuclear translocation in cultured cortical neurons following heat stress or oxygen–glucose deprivation

Anderson

Meeker

Poulton

et al. 2010

Cell Stress and Chaperones

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Carboxy terminus of Hsc70-interacting protein (CHIP) is thought to be a cytoprotective protein with protein quality control roles in neurodegenerative diseases and myocardial ischemia. This study describes the localization of CHIP expression in normal rodent brain and the early CHIP response in primary cultures of cortical neurons following ischemic stress models: heat stress (HS) and oxygen-glucose deprivation (OGD). CHIP was highly expressed throughout the brain, predominantly in neurons. The staining pattern was primarily cytoplasmic, although small amounts were seen in the nucleus. More intense nuclear staining was observed in primary cultured neurons which increased with stress. Nuclear accumulation of CHIP occurred within 5-10 min of HS and decreased to baseline levels or lower by 30-60 min. Decrease in nuclear CHIP at 30-60 min of HS was associated with a sharp increase in delayed cell death. While no changes in cytoplasmic CHIP were observed immediately following OGD, nuclear levels of CHIP increased slightly in response to OGD durations of 30 to 240 min. OGD-induced increases in nuclear CHIP decreased slowly during post-ischemic recovery. Nuclear CHIP decreased earlier in recovery following 120 min of OGD (4 h) than 30 min of OGD (12 h). Significant cell death first appeared between 12 and 24 h after OGD, again suggesting that delayed cell death follows closely behind the disappearance of nuclear CHIP. The ability of CHIP to translocate to and accumulate in the nucleus may be a limiting variable that determines how effectively cells respond to external stressors to facilitate cell survival. Using primary neuronal cell cultures, we were able to demonstrate rapid translocation of CHIP to the nucleus within minutes of heat stress and oxygen-glucose deprivation. An inverse relationship between nuclear CHIP and delayed cell death at 24 h suggests that the decrease in nuclear CHIP following extreme stress is linked to delayed cell death. Our findings of acute changes in subcellular localization of CHIP in response to cellular stress suggest that cellular changes that occur shortly after exposure to stress ultimately impact on the capacity and capability of a cell to recover and survive.

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Section: Discussionsupporting

confidence: 74%

Brain distribution of carboxy terminus of Hsc70-interacting protein (CHIP) and its nuclear translocation in cultured cortical neurons following heat stress or oxygen–glucose deprivation

Anderson

Meeker

Poulton

et al. 2010

Cell Stress and Chaperones

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“…We therefore analyzed the hippocampus and parietal cortex subcellular fractions by Western blotting with antibodies to phospho-rpS6 Ser 235/236 and total rpS6. Similar to ribosomal subcellular distribution, rpS6 was present in crude synaptosome subcellular fractions (P12P and P12S) and the microsomal fraction (Liu et al, 2005 Phosphorylation of mTOR was significantly increased 30 mins after TBI in the ipsilateral hippocampus (Hipp; n = 4 for each group, P < 0.05) and parietal cortex (Cx; n = 4 for each group, P < 0.001). (B) Total mTOR levels in the crude synaptosome subcellular fractions did not significantly change in either the ipsilateral hippocampus (n = 4 for each group) or parietal cortex (n = 4 for each group) after TBI.…”

Section: Resultsmentioning

confidence: 77%

Alterations in Mammalian Target of Rapamycin Signaling Pathways after Traumatic Brain Injury

Chen

Atkins

Liu

et al. 2006

J Cereb Blood Flow Metab

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In response to traumatic brain injury (TBI), neurons initiate neuroplastic processes through the activation of intracellular signaling pathways. However, the molecular mechanisms underlying neuroplasticity after TBI are poorly understood. To study this, we utilized the fluid-percussion brain injury (FPI) model to investigate alterations in the mammalian target of rapamycin (mTOR) signaling pathways in response to TBI. Mammalian target of rapamycin stimulates mRNA translation through phosphorylation of eukaryotic initiation factor 4E binding protein-1 (4E-BP1), p70 ribosomal S6 kinase (p70S6K), and ribosomal protein S6 (rpS6). These pathways coordinate cell growth and neuroplasticity via dendritic protein synthesis. Rats received sham surgery or moderate parasagittal FPI on the right side of the parietal cortex, followed by 15 mins, 30 mins, 4 h, 24 h, or 72 h of recovery. Using Western blot analysis, we found that mTOR, p70S6K, rpS6, and 4E-BP1 phosphorylation levels were significantly increased in the ipsilateral parietal cortex and hippocampus from 30 mins to 24 h after TBI, whereas total protein levels were unchanged. Using confocal microscopy to localize these changes, we found that rpS6 phosphorylation was increased in the parietal cortex and all subregions of the hippocampus. In accordance with these results, eIF4E, a key, rate-limiting mRNA translation factor, was also phosphorylated by mitogen-activated protein kinase-interacting kinase 1 (Mnk1) 15 mins after TBI. Together, these results suggest that changes in mRNA translation may be one mechanism that neurons use to respond to trauma and may contribute to the neuroplastic changes observed after TBI.

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“…[35][36][37] The initiation factor eIF3 and the chaperons HSP40 and HSC70 were earlier reported to be trapped in postischemic protein aggregates. 16 We also found that many initiation and elongation factors and various chaperons were ubiquitylated after ischemia and trapped in Triton X-100-insoluble aggregates. Further, the calcium-binding protein hippocalcin was highly ubiquitylated after ischemia.…”

Section: Proteomics Of Postischemic Ubiquitin Aggregates M Iwabuchi Ementioning

confidence: 74%

Characterization of the Ubiquitin-Modified Proteome Regulated by Transient Forebrain Ischemia

Iseki

Sheng

Thompson³

et al. 2013

J Cereb Blood Flow Metab

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Ubiquitylation is a posttranslational protein modification that modulates various cellular processes of key significance, including protein degradation and DNA damage repair. In animals subjected to transient cerebral ischemia, ubiquitin-conjugated proteins accumulate in Triton-insoluble aggregates. Although this process is widely considered to modulate the fate of postischemic neurons, few attempts have been made to characterize the ubiquitin-modified proteome in these aggregates. We performed proteomics analyses to identify ubiquitylated proteins in postischemic aggregates. Mice were subjected to 10 minutes of forebrain ischemia and 4 hours of reperfusion. The hippocampi were dissected, aggregates were isolated, and trypsin-digested after spiking with GG-BSA as internal standard. K-e-GG-containing peptides were immunoprecipitated and analyzed by label-free quantitative liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. We identified 1,664 peptides to 520 proteins containing at least one K-e-GG. Sixty-six proteins were highly ubiquitylated, with 10 or more K-e-GG peptides. Based on selection criteria of greater than fivefold increase and Po0.001, 763 peptides to 272 proteins were highly enriched in postischemic aggregates. These included proteins involved in important neuronal functions and signaling pathways that are impaired after ischemia. Results of this study could serve as an important platform to uncover the mechanisms linking insoluble ubiquitin aggregates to the functions of postischemic neurons.

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Co-translational protein aggregation after transient cerebral ischemia

Cited by 70 publications

References 37 publications

Brain distribution of carboxy terminus of Hsc70-interacting protein (CHIP) and its nuclear translocation in cultured cortical neurons following heat stress or oxygen–glucose deprivation

Brain distribution of carboxy terminus of Hsc70-interacting protein (CHIP) and its nuclear translocation in cultured cortical neurons following heat stress or oxygen–glucose deprivation

Alterations in Mammalian Target of Rapamycin Signaling Pathways after Traumatic Brain Injury

Characterization of the Ubiquitin-Modified Proteome Regulated by Transient Forebrain Ischemia

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