Proteasome inhibition results in increased poly-ADP-ribosylation: Implications for neuron death

Keller, Jeffrey N.; Markesbery, William R.

doi:10.1002/1097-4547(20000815)61:4<436::aid-jnr10>3.0.co;2-z

Cited by 50 publications

(43 citation statements)

References 46 publications

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“…Furthermore, injection of a proteasome inhibitor into the lateral ventricle of rats significantly decreased NF-kB activity and resulted in apoptotic neuronal death in various CNS areas, suggesting that proteasome inhibition induces apoptotic neuronal death (Taglialatela et al, 1998). Also, incubation of different types of neurons with proteasome inhibitors was shown to induce cell death (Keller and Markesbery, 2000;Qiu et al, 2000;Bobba et al, 2002;Ding et al, 2006). These results would further suggest that proteasome inhibition contributes to neuronal death in brain ischemia.…”

Section: Protective Effects Of Proteasome Modulators In Brain Ischemiamentioning

confidence: 86%

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

Caldeira

Salazar

Curcio

et al. 2014

Progress in Neurobiology

114

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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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Section: Protective Effects Of Proteasome Modulators In Brain Ischemiamentioning

confidence: 86%

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

Caldeira

Salazar

Curcio

et al. 2014

Progress in Neurobiology

114

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“…Previous studies have utilized proteasome inhibitors to elucidate the role of the proteasome in degradation of various substrates, including GFP-and polyglutamine-containing proteins (14,19,41,47). However, it is important to point out that proteasome inhibitors are highly toxic to many cells, including neurons and neural cell lines (22)(23)(24), and that the effects of proteasome inhibition may ultimately be due to induction of cell death process and not proteasome inhibition per se.…”

Section: Discussionmentioning

confidence: 99%

“…The proteasome also appears to be particularly important in the degradation of polyglutamineenriched and readily aggregating proteins (19 -21). Because proteasome inhibition is sufficient to induce neuron death in vitro (22)(23)(24), and numerous reports have now demonstrated proteasome inhibition in a wide range of neurodegenerative conditions (25)(26)(27)(28), it is plausible that proteasome inhibition may play a role in polyglutamine disorders. However, at present the characterization of proteasome inhibition, and role of proteasome inhibition in polyglutamine disorders, has not been fully elucidated.…”

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confidence: 99%

Polyglutamine Expansion, Protein Aggregation, Proteasome Activity, and Neural Survival

Qian¹,

Lewis²,

Strum³

et al. 2002

Journal of Biological Chemistry

Self Cite

103

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Huntington's disease (HD) is one of eight established triplet repeat neurodegenerative disorders, which are collectively caused by the genetic expansion of polyglutamine repeats. While the mechanism(s) by which polyglutamine expansion causes neurodegeneration in each of these disorders is being intensely investigated, the underlying cause of polyglutamine toxicity has not been fully elucidated. A number of studies have focused on the potential role of protein aggregation and disruption of the proteasome proteolytic pathway in polyglutamine-mediated neurodegeneration. However, at present it is not clear whether polyglutamine-mediated protein aggregation is sufficient to induce cell death, nor has it been clearly determined whether proteasome inhibition precedes, coincides, or occurs as the result of the formation of polyglutamine-associated protein aggregation. To address these important components of polyglutamine toxicity, in the present study we utilized neural SH-SY5Y cells stably transfected with polyglutamine-green fluorescent protein constructs to examine the effects of polyglutamine expansion on protein aggregation, proteasome activity, and neural cell survival. Data from the present study demonstrate that polyglutamine expansion does not dramatically impair proteasome activity or elevate protein aggregate formation under basal conditions, but does significantly impair the ability of the proteasome to respond to stress, and increases stress-induced protein aggregation following stress, all in the absence of neural cell death.

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“…[51][52][53] Activity and expression of brain proteasomes decrease in neurodegenerative disorders and with age, contributing to the elevations in protein oxidation, protein aggregation, and neurodegeneration evident in the aging CNS. 54,55 Alterations of ubiquitination of specific substrates caused by mutations of appropriate E3s are often associated with different neurological diseases. 56 -58 …”

Section: Ups In the Central Nervous Systemmentioning

confidence: 99%

Ubiquitin-Proteasome System and Proteasome Inhibition: New Strategies in Stroke Therapy

Wojcik

Napoli

2004

Stroke

122

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Background and Purpose-Proteasomes are large multicatalytic proteinase complexes that are found in the cytosol and in the nucleus of eukaryotic cells with a central role in cellular protein turnover. The ubiquitin-proteasome system (UPS) has a central role in the selective degradation of intracellular proteins. Among the key proteins whose levels are modulated by the proteasome are those involved in the control of inflammatory processes, cell cycle regulation, and gene expression. There are now overwhelming data suggesting that the UPS contributes to cerebral ischemic injury. Summary of Review-Proteasome inhibition is a potential treatment option for stroke. Thus far, proof of principle has been obtained from studies in several animal models of cerebral ischemia. Treatment with proteasome inhibitors reduces effectively neuronal and astrocytic degeneration, cortical infarct volume, infarct neutrophil infiltration, and NF-B immunoreactivity with an extension of the neuroprotective effect at least 6 hours after ischemic insult. However, it is clear that the UPS represents a central pathway for the processing and metabolism of multiple proteins with critical roles in cellular function. To avoid eliciting significant side effects associated with complete inhibition of the proteasome and the possible immunosuppressive effects from persistent suppression of NF-B activation, it is critical that we understand how to partially and temporally attenuate proteasome function to elicit the desired therapeutic effect before any large-scale use in humans. Conclusion-This review highlights the most recent advances in our knowledge on UPS, as well as the early experience of using proteasome inhibition strategies to treat acute stroke.

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Proteasome inhibition results in increased poly-ADP-ribosylation: Implications for neuron death

Cited by 50 publications

References 46 publications

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

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

Polyglutamine Expansion, Protein Aggregation, Proteasome Activity, and Neural Survival

Ubiquitin-Proteasome System and Proteasome Inhibition: New Strategies in Stroke Therapy

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