Monteiro F A, Sousa M M, Cardoso I, do Amaral J Barbas, Guimarães A, Saraiva M J
Molecular Neurobiology, Instituto de Biologia Celular e Molecular, ICBAS, University of Porto, and Estomatology, Maxillofacial Surgery, Hospital Geral de Santo António, Portugal.
J Neurochem. 2006 Apr;97(1):151-61. doi: 10.1111/j.1471-4159.2006.03716.x. Epub 2006 Mar 3.
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.
家族性淀粉样多神经病（FAP）是一种神经退行性疾病，其特征是转甲状腺素蛋白（TTR）在细胞外沉积，尤其是在周围神经系统（PNS）。鉴于神经活检具有侵入性，FAP患者的唾液腺（SG）先前被用于微阵列分析；丝裂原活化蛋白（MAP）激酶磷酸酶1（MKP-1）在FAP中表达下调。结果通过逆转录聚合酶链反应（RT-PCR）和免疫组织化学在SG以及疾病进展不同阶段患者的神经活检中均得到验证。MKP-3在FAP的SG活检中也表达下调。鉴于MKP与MAPK之间的关系，对后者进行了研究。仅细胞外信号调节激酶1/2（ERK1/2）在FAP的SG和神经中显示出激活增加。FAP神经中ERK1/2激酶（MEK1/2）的激活也上调。此外，与对照动物相比，FAP转基因小鼠模型显示，在受TTR沉积影响的周围神经中ERK1/2激活增加。用TTR聚集体处理培养的大鼠雪旺氏细胞瘤细胞系可刺激ERK1/2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消除了TTR聚集体触发的半胱天冬酶-3激活，表明ERK1/2激活对于TTR聚集体诱导的细胞毒性至关重要。综上所述，这些数据表明FAP中ERK的异常持续激活可能代表导致神经退行性变的早期信号级联反应。
