Molecular mechanism of neuronal cell death in Alzheimer's disease

阿尔茨海默病（AD）中的选择性神经元变性尚未得到广泛研究，主要是由于神经元亚群的特异性组织学或分子标记物很少。此外，参与神经元变性的细胞内信号通路仍有待分析。JNK 3是丝裂原活化蛋白激酶的成员，在人类神经系统的神经元亚群中表达。这些神经元的分布与AD靶向神经元的分布紧密匹配。作为阐明JNK 3级联反应的第一步，我们利用酵母双杂交系统分离了JNK 3结合蛋白的cDNA克隆。其中一种JNK 3结合蛋白（称为BP#2）仅在脑中表达为JNK 3。BP#2可以是JNK 3的底物，并且磷酸化的BP#2不再与活化的JNK 3结合。此外，我们发现BP#2不仅与JNK 3相关，而且与JNK 3的激活剂SEK 1相关。这些结果表明BP#2在JNK 3级联中作为支架蛋白发挥作用。JNK 3/BP#2复合物将通过JNK 3完成的BP#2的磷酸化而解离。

The selective neuronal degeneration in Alzheimer's disease (AD) has not been extensively studied, mainly due to few specific histological or molecular markers for neuronal subpopulations. Moreover, the intracellular signaling pathway involved in the neuronal degeneration remains to be analyzed. JNK3, a member of mitogen-activated protein kinase, expresses in a subset of neurons of the human nervous system. The distribution of these neurons closely matches that of AD targeted neurons. As a first step to clarify the JNK3 cascade, we have carried out yeast two-hybrid system to isolate cDNA clones of JNK3-binding proteins. One of the JNK3-binding proteins (termed BP#2) expresses exclusively in brain as JNK3. BP#2 can be a sustrate of JNK3, and the phosphorylated BP#2 no longer binds with the activated JNK3. Furthermore, we have found that BP#2 associates with not only JNK3 but also SEK1, an activator of JNK3. These results suggest that BP#2 works as a scaffold protein in the JNK3 cascade. The JNK3/BP#2 complex would dissociate through the phosphorylation of BP#2 done by JNK3.