Irreversible aggregation of protein synthesis machinery after focal brain ischemia

Zhang, Fan; Liu, C. L.; Hu, Bing

doi:10.1111/j.1471-4159.2006.03838.x

Cited by 53 publications

(92 citation statements)

References 47 publications

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“…One possibility is that CHIP may become trapped within protein aggregates. 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.…”

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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“…21 We have previously proposed that protein unfolding and aggregation after brain ischemia reflect a quantitative imbalance between the amounts of toxic unfolded proteins and the capacity of protein quality control systems to eliminate them. [7][8][9] Therefore, this study provides new evidence that ischemia-induced proteasome dysfunction contributes, at least in part, to delayed neuronal death after brain ischemia.…”

Section: Proteasomal Dysfunction and Delayed Neuronal Deathmentioning

confidence: 68%

“…We have previously demonstrated that molecular chaperones are irreversibly malfunctioning, leading to large amounts of unfolded proteins without chaperone protection in postischemic neurons. [7][8][9] Without chaperone protection, unfolded polypeptides and their associated cellular machinery remain abnormal (toxic) and must be eliminated by the proteasome system after brain ischemia. However, ubiproteins after brain ischemia are too numerous to be degraded by the compromised proteasomes; they eventually aggregate after an episode of brain ischemia.…”

Section: Proteasomal Disassembly and Aggregationmentioning

confidence: 99%

“…4 However, under electron microscopy (EM), a dominant pathologic event is the continuous accumulation of ubiquitin-conjugated protein (ubiprotein) aggregates, which takes place mainly in vulnerable ischemic neurons from the onset of reperfusion onward until delayed neuronal death occurs after 2 to 3 days of reperfusion. [5][6][7][8][9] To study whether overproduction of ubiproteins after brain ischemia is due to proteasome dysfunction, we investigated proteasome activity, disassembly, and deposition into protein aggregates after brain ischemia. This study suggests that unfolded proteins are too numerous to be degraded by proteasomes, but they trap the "escorting" proteasomes into their aggregates after brain ischemia.…”

mentioning

confidence: 99%

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Protein Aggregation and Proteasome Dysfunction After Brain Ischemia

Luo

Liu

et al. 2007

Stroke

105

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Background and Purpose-Protein unfolding and aggregation are dominant early pathogenic events in neurons after brain ischemia. This study used a transient cerebral ischemia model to investigate whether overproduction of unfolded proteins after brain ischemia is a consequence of proteasome dysfunction. Methods-Proteasome peptidase activity and proteasome subcellular redistribution and assembly were studied by peptidase activity assay, Western blot analysis, and size-exclusion chromatography. Results-Proteasome peptidase activity, as determined with the peptide substrate succinyl-LLVY-7-amino-4-methylcoumarin, was moderately decreased, and the 26S proteasome was disassembled during the early period of reperfusion after transient brain ischemia. Furthermore, the proteasome subunits, particularly the 19S components, were deposited into the protein aggregate-containing fraction after an episode of transient cerebral ischemia. Conclusions-These results clearly demonstrate that after an episode of brain ischemia, proteasomes are disassembled and aggregated and thus fail to function normally. Deposition of proteasomes into protein aggregates may also indicate that proteasomes attempt to degrade ubiquitin-conjugated proteins (ubiproteins) overproduced after brain ischemia. However, ubiproteins are too numerous to be degraded and trap some of the proteasomes into their aggregates after brain ischemia. (Stroke. 2007;38:3230-3236.)

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“…In fact, translational complex components are irreversibly clumped into large abnormal protein aggregates after transient brain ischemia (Liu et al, 2005) or focal brain ischemia (Zhang et al, 2006a), suggesting that the irreversible inhibition of translation in neurons destined to die after ischemia is caused by irreversible aggregation of translational complex components, chaperones and protein folding enzymes. Moreover, proteasomes, particularly the 19S RP, are also sequestered into these protein aggregates in post-ischemic brains (Ge et al, 2007).…”

Section: Ups and In Vivo Ischemia Modelsmentioning

confidence: 99%

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Caldeira

Salazar

Curcio

et al. 2014

Progress in Neurobiology

113

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A B S T R A C TThe ubiquitin-proteasome system (UPS) is a catalytic machinery that targets numerous cellular proteins for degradation, thus being essential to control a wide range of basic cellular processes and cell survival. Degradation of intracellular proteins via the UPS is a tightly regulated process initiated by tagging a target protein with a specific ubiquitin chain. Neurons are particularly vulnerable to any change in protein composition, and therefore the UPS is a key regulator of neuronal physiology. Alterations in UPS activity may induce pathological responses, ultimately leading to neuronal cell death. Brain ischemia triggers a complex series of biochemical and molecular mechanisms, such as an inflammatory response, an exacerbated production of misfolded and oxidized proteins, due to oxidative stress, and the breakdown of cellular integrity mainly mediated by excitotoxic glutamatergic signaling. Brain ischemia also damages protein degradation pathways which, together with the overproduction of damaged proteins and consequent upregulation of ubiquitin-conjugated proteins, contribute to the accumulation of ubiquitincontaining proteinaceous deposits. Despite recent advances, the factors leading to deposition of such aggregates after cerebral ischemic injury remain poorly understood. This review discusses the current knowledge on the role of the UPS in brain function and the molecular mechanisms contributing to UPS dysfunction in brain ischemia with consequent accumulation of ubiquitin-containing proteins. Chemical inhibitors of the proteasome and small molecule inhibitors of deubiquitinating enzymes, which promote the degradation of proteins by the proteasome, were both shown to provide neuroprotection in brain ischemia, and this apparent contradiction is also discussed in this review. ß

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Irreversible aggregation of protein synthesis machinery after focal brain ischemia

Cited by 53 publications

References 47 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

Protein Aggregation and Proteasome Dysfunction After Brain Ischemia

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

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