Cytoplasmic aggregates of phosphorylated extracellular signal-regulated protein kinases in Lewy body diseases.
Cytoplasmic aggregates of phosphorylated extracellular signal-regulated protein kinases in Lewy body diseases.
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DOI：
10.1016/s0002-9440(10)64487-2
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发表时间：
2002-12
期刊：
影响因子：
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通讯作者：
Jian‐hui Zhu;S. Kulich;T. Oury;C. Chu
中科院分区：
文献类型：
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作者：
Jian‐hui Zhu;S. Kulich;T. Oury;C. Chu
更好地了解帕金森病和相关路易体疾病中发生的细胞机制对于开发新疗法至关重要。我们之前发现，6-羟基多巴胺 (6-OHDA) 会引起持续的细胞外信号调节激酶 (ERK) 激活，从而导致体外神经细胞死亡。由于活化激酶的亚细胞定位影响下游靶标的可及性，我们检查了 6-OHDA 处理的细胞和代表路易体疾病全谱的人类死后组织中 ERK 磷酸化的空间模式。所有患病的人类病例在黑质（涉及 28 ± 2% 的神经元）中都表现出惊人的磷酸 ERK (P-ERK) 颗粒状细胞质聚集体，而在对照病例中则基本不存在 (0.3 ± 0.3%)。双标记研究和临床前病例检查表明这些 P-ERK 改变可能发生在疾病过程的相对早期。 6-OHDA 处理的细胞中颗粒细胞质 P-ERK 染色的发展被神经保护剂量的过氧化氢酶阻断，这支持了氧化剂在引发 ERK 激活的神经毒性模式中的作用。在退化神经元中没有观察到核易位的证据。此外，颗粒细胞质 P-ERK 与下游靶标（如 P-RSK1）分布的改变相关，但与 P-Elk-1 无关，表明路易体疾病中 ERK 信号通路的功能转移。
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.