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

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 <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.

CHIP Is an Essential Determinant of Neuronal Mitochondrial Stress Signaling

“…We detected no change in Parkin or voltage-dependent anion channel (VDAC) expression in response to OGD in vitro, which is in keeping with results from other labs, which demonstrate that Parkin is poorly inducible in cortical neuronal cultures exposed to endoplasmic reticulum stress (34). We did, however, observe increases in LC3-I and LC3-II, the major components of autophagosomes (Figs.…”

Caspase-1 and Caspase-8 Cleave and Inactivate Cellular Parkin

“…This is corroborated by the detection of cleaved parkin fragments in substantia nigral tissue affected by Parkinson's disease and in Lewy bodies isolated from diseased tissue (30,31). Moreover, proteolytic inactivation of parkin may play a broader role in neurodegenerative settings as recently demonstrated by parkin's rapid catabolism upon hypoxia (32). Growing evidence suggests that inappropriate activation of apoptotic processes is involved in the pathology of degenerative diseases, including sporadic Parkinson's disease (13,33), and caspase activation could represent a link to parkin dysfunction in sporadic Parkinson's disease.…”

Killer Proteases and Little Strokes—How the Things that do not Kill You Make You Stronger

“…One hour transient focal cerebral ischemia induces marked depletion of the E3 ligase Parkin but does not affect the levels of E2 conjugating enzymes (Mengesdorf et al, 2002). Parkin upregulation has been shown to protect cells from injury induced by ER stress.…”