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Cytoplasmic aggregates of phosphorylated extracellular signal-regulated protein kinases in Lewy body diseases.
A better understanding of cellular mechanisms that occur in Parkinson's disease and related Lewy body diseases is essential for development of new therapies. We previously found that 6-hydroxydopamine (6-OHDA) elicits sustained extracellular signal-regulated kinase ( ERK) activation that contributes to neuronal cell death in vitro. As subcellular localization of activated kinases affect accessibility to downstream targets, we examined spatial patterns of ERK phosphorylation in 6-OHDA-treated cells and in human postmortem tissues representing the full spectrum of Lewy body diseases. All diseased human cases exhibited striking granular cytoplasmic aggregates of phospho-ERK (P- ERK) in the substantia nigra (involving 28 +/- 2% of neurons), which were largely absent in control cases (0.3 +/- 0.3%). Double-labeling studies and examination of preclinical cases suggested that these P- ERK alterations could occur relatively early in the disease process. Development of granular cytoplasmic P- ERK staining in 6-OHDA-treated cells was blocked by neuroprotective doses of catalase, supporting a role for oxidants in eliciting neurotoxic patterns of ERK activation. Evidence of nuclear translocation was not observed in degenerating neurons. Moreover, granular cytoplasmic P- ERK was associated with alterations in the distribution of downstream targets such as P-RSK1, but not of P-Elk-1, suggesting functional diversion of ERK-signaling pathways in Lewy body diseases.[1]References
- Cytoplasmic aggregates of phosphorylated extracellular signal-regulated protein kinases in Lewy body diseases. Zhu, J.H., Kulich, S.M., Oury, T.D., Chu, C.T. Am. J. Pathol. (2002)
