Peroxidative stress selectively down‐regulates the neuronal stress response activated under conditions of endoplasmic reticulum dysfunction

Paschen, Wulf; Mengesdorf, Thorsten; Althausen, Sonja; Hotop, S.

doi:10.1046/j.1471-4159.2001.00206.x

Cited by 64 publications

(40 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…GRP78 and GRP94 (78 and 94 kDa glucoseregulated proteins) are two endoplasmic reticulumlocated molecular chaperones that participate in the antioxidative stress response (39,40). In this study, we measured both GRP78 and GRP94 protein levels in Pb and/or Cu-exposed astroglia.…”

Section: Resultsmentioning

confidence: 99%

The Involvement of Copper Transporter in Lead-induced Oxidative Stress in Astroglia

et al. 2005

View full text Add to dashboard Cite

Lead (Pb), depositing primarily in astroglia in the brain, is a well-known neurotoxicant and a risk factor for neurologic disorders. Pb has been reported to induce oxidative stress by probably the disturbance of copper (Cu) homeostasis in astroglia. Thus, we hypothesized that Pb-induced oxidative stress is initiated by interfering with Cu transporter in astroglia. In this study, we observed Pb-induced oxidative stress as indicated by reactive oxygen species (ROS) augmentation and GRP78 and GRP94 protein induction, and it was parallel to Cu accumulation intracellularly by Pb. To further address Cu transporter as a potential Pb target, a heavy metal-binding (HMB) domain of Cu-transporting ATPase (Atp7a) was overexpressed and purified. Evidence showed that one molecule of HMB chelated 11 Pb ions or seven Cu ions and that Pb competed with Cu for binding to HMB. These findings suggest that Pb-induced oxidative stress results from the impairment of Cu metabolism by Pb targeting of Atp7a.

show abstract

Section: Resultsmentioning

confidence: 99%

The Involvement of Copper Transporter in Lead-induced Oxidative Stress in Astroglia

et al. 2005

View full text Add to dashboard Cite

show abstract

“…Less is known about the regulation of SERCA activity in brain, where it occurs at much lower levels than in muscle (41), but a number of studies, mainly using thapsigargin, have shown that SERCA plays a crucial role in neuronal function. For instance, exposure of neurons and neuronal cell lines to thapsigargin results in ER stress (42,43), decreased neuronal viability (8, 9), inhibition of protein synthesis (44), and injury in developing nerves (45).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Calcium Uptake via the Sarco/Endoplasmic Reticulum Ca2+-ATPase in a Mouse Model of Sandhoff Disease and Prevention by Treatment with N-Butyldeoxynojirimycin

Pelled

Lloyd-Evans

Riebeling

et al. 2003

Journal of Biological Chemistry

131

107

View full text Add to dashboard Cite

Gangliosides are found at high levels in neuronal tissues where they play a variety of important functions. In the gangliosidoses, gangliosides accumulate because of defective activity of the lysosomal proteins responsible for their degradation, usually resulting in a rapidly progressive neurodegenerative disease. However, the molecular mechanism(s) leading from ganglioside accumulation to neurodegeneration is not known. We now examine the effect of ganglioside GM2 accumulation in a mouse model of Sandhoff disease (one of the GM2 gangliosidoses), the Hexb؊/؊ mouse. Microsomes from Hexb؊/؊ mouse brain showed a significant reduction in the rate of Ca 2؉ -uptake via the sarco/endoplasmic reticulum Ca 2؉ -ATPase (SERCA), which was prevented by feeding Hexb؊/؊ mice with N-butyldeoxynojirimycin (NB-DNJ), an inhibitor of glycolipid synthesis that reduces GM2 storage. Changes in SERCA activity were not due to transcriptional regulation but rather because of a decrease in V max . Moreover, exogenously added GM2 had a similar effect on SERCA activity. The functional significance of these findings was established by the enhanced sensitivity of neurons cultured from embryonic Hexb؊/؊ mice to cell death induced by thapsigargin, a specific SERCA inhibitor, and by the enhanced sensitivity of Hexb؊/؊ microsomes to calcium-induced calcium release. This study suggests a mechanistic link among GM2 accumulation, reduced SERCA activity, and neuronal cell death, which may be of significance for delineating the neuropathophysiology of Sandhoff disease.

show abstract

“…Changes in parkin mRNA levels of cultures exposed to Tg were evaluated by quantitative PCR as described (19,20). The following parkin primers were used: (sequence taken from GenBank, accession no.…”

Section: Methodsmentioning

confidence: 99%

Down-regulation of parkin protein in transient focal cerebral ischemia: A link between stroke and degenerative disease?

Mengesdorf

Jensen

Mies

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Ubiquitylated protein aggregates are characteristic features of neurodegenerative disorders that are also found in acute pathological states of the brain such as stroke. Many of the proteins connected to neurodegenerative diseases play a role in the ubiquitin-proteasomal pathway. Mutation of one of these proteins, the E3 ubiquitin ligase parkin, is the cause of autosomal recessive juvenile Parkinson's disease. Here we show that transient focal cerebral ischemia of 1-h duration induces marked depletion of parkin protein levels, to 60%, 36%, 33%, and 25% of controls after 1, 3, 6, and 24 h of reperfusion, but that ischemia does not cause lower protein levels of E2 ubiquitin-conjugating enzymes Ubc6, Ubc7, or Ubc9. After 3 h of reperfusion, when parkin protein levels were already reduced to <40% of control, ATP levels were almost completely recovered from ischemia and we did not observe DNA fragmentation, suggesting that parkin depletion preceded development of neuronal cell death. Up-regulation of the expression of parkin has been shown to protect cells from injury induced by endoplasmic reticulum (ER) dysfunction, and this form of cellular stress is also triggered by transient cerebral ischemia. However, in contrast to observations in neuroblastoma cells, we saw no upregulation of parkin expression in primary neuronal cell cultures after induction of ER dysfunction. Our data thus suggest that ischemia-induced depletion of parkin protein may contribute to the pathological process resulting in cell injury by increasing the sensitivity of neurons to ER dysfunction and the aggregation of ubiquitylated proteins during the reperfusion period.

show abstract

Peroxidative stress selectively down‐regulates the neuronal stress response activated under conditions of endoplasmic reticulum dysfunction

Cited by 64 publications

References 63 publications

The Involvement of Copper Transporter in Lead-induced Oxidative Stress in Astroglia

The Involvement of Copper Transporter in Lead-induced Oxidative Stress in Astroglia

Inhibition of Calcium Uptake via the Sarco/Endoplasmic Reticulum Ca2+-ATPase in a Mouse Model of Sandhoff Disease and Prevention by Treatment with N-Butyldeoxynojirimycin

Down-regulation of parkin protein in transient focal cerebral ischemia: A link between stroke and degenerative disease?

Contact Info

Product

Resources

About