http://www.pnas.org/content/99/23/15042.short
Abstract
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 less than 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 up-regulation 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.
And maybe a fix for this particular problem.
After 3 h of reperfusion, when parkin protein levels were already reduced to less than 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 up-regulation 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.
And maybe a fix for this particular problem.
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