Activation of ERK1/2 MAP kinases in familial amyloidotic polyneuropathy
Activation of ERK1/2 MAP kinases in familial amyloidotic polyneuropathy
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DOI：
10.1111/j.1471-4159.2006.03716.x
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发表时间：
2006-04-01
影响因子：
4.7
通讯作者：
Saraiva, MJ
中科院分区：
文献类型：
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作者：
Monteiro, FA;Sousa, MM;Saraiva, MJ
家族性淀粉样变性多发性神经病(FAP)是一种神经退行性疾病，其特征是细胞外跨甲状腺激素(TTR)沉积，尤其是在三叉神经节。考虑到神经活检的侵袭性，FAP患者的唾液腺(SG)先前被用于微阵列分析；丝裂原激活蛋白(MAP)激酶磷酸酶1(MKP-1)在FAP中下调。用RT-PCR和免疫组织化学方法验证了SG和疾病进展不同阶段的神经活检组织中的结果。MKP-3在FAP SG组织中表达下调。鉴于MKPs和MAPKs之间的关系，对后者进行了研究。只有细胞外信号调节蛋白1/2(ERK1/2)在FAP、SG和神经中的激活增加。ERK1/2激酶(MEK1/2)在FAP神经中的激活也上调。此外，FAP转基因小鼠模型显示，与对照动物相比，受TTR沉积影响的周围神经中ERK1/2激活增加。培养的大鼠神经鞘瘤细胞系经TTR聚合体处理后，ERK1/2被激活，这部分是由晚期糖基化终产物受体(RAGE)介导的。此外，MEK1/2抑制剂U0126可阻断TTR聚集体触发的caspase-3激活，表明ERK1/2的激活在TTR聚集体诱导的细胞毒作用中是必不可少的。综上所述，这些数据表明，FAP中ERK的异常持续激活可能代表了导致神经变性的早期信号级联反应。
Familial amyloidotic polyneuropathy (FAP) is a neurodegenerative disorder characterized by the extracellular deposition of transthyretin (TTR), especially in the PNS. Given the invasiveness of nerve biopsy, salivary glands (SG) from FAP patients were used previously in microarray analysis; mitogen-activated protein (MAP) kinase phosphatase 1 (MKP-1) was down-regulated in FAP. Results were validated by RT-PCR and immunohistochemistry both in SG and in nerve biopsies of different stages of disease progression. MKP-3 was also down-regulated in FAP SG biopsies. Given the relationship between MKPs and MAPKs, the latter were investigated. Only extracellular signal-regulated kinases 1/2 (ERK1/2) displayed increased activation in FAP SG and nerves. ERK1/2 kinase (MEK1/2) activation was also up-regulated in FAP nerves. In addition, an FAP transgenic mouse model revealed increased ERK1/2 activation in peripheral nerve affected with TTR deposition when compared to control animals. Cultured rat Schwannoma cell line treatment with TTR aggregates stimulated ERK1/2 activation, which was partially mediated by the receptor for advanced glycation end-products (RAGE). Moreover, caspase-3 activation triggered by TTR aggregates was abrogated by U0126, a MEK1/2 inhibitor, indicating that ERK1/2 activation is essential for TTR aggregates-induced cytotoxicity. Taken together, these data suggest that abnormally sustained activation of ERK in FAP may represent an early signaling cascade leading to neurodegeneration.