Cole Adam R, Knebel Axel, Morrice Nick A, Robertson Laura A, Irving Andrew J, Connolly Chris N, Sutherland Calum
Division of Pathology and Neurosciences, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, Scotland.
J Biol Chem. 2004 Nov 26;279(48):50176-80. doi: 10.1074/jbc.C400412200. Epub 2004 Oct 5.
Elevated glycogen synthase kinase-3 (GSK-3) activity is associated with Alzheimer disease. We have found that collapsin response mediator proteins (CRMP) 2 and 4 are physiological substrates of GSK-3. The amino acids targeted by GSK-3 comprise a hyperphosphorylated epitope first identified in plaques isolated from Alzheimer brain. Expression of wild type CRMP2 in primary hippocampal neurons or SH-SY5Y neuroblastoma cells promotes axon elongation. However, a GSK-3-insensitive CRMP2 mutant has dramatically reduced ability to promote axon elongation, a similar effect to pharmacological inhibition of GSK-3. Hence, we propose that phosphorylation of CRMP proteins by GSK-3 regulates axon elongation. This work provides a direct connection between hyperphosphorylation of these residues and elevated GSK-3 activity, both of which are observed in Alzheimer brain.
糖原合酶激酶-3（GSK-3）活性升高与阿尔茨海默病相关。我们发现，塌陷反应介导蛋白（CRMP）2和4是GSK-3的生理底物。GSK-3作用的氨基酸包含一个高磷酸化表位，该表位最初在从阿尔茨海默病大脑分离出的斑块中被鉴定出来。野生型CRMP2在原代海马神经元或SH-SY5Y神经母细胞瘤细胞中的表达促进轴突伸长。然而，一种对GSK-3不敏感的CRMP2突变体促进轴突伸长的能力显著降低，这与GSK-3的药理学抑制作用类似。因此，我们提出GSK-3对CRMP蛋白的磷酸化调节轴突伸长。这项工作在这些残基的高磷酸化与升高的GSK-3活性之间建立了直接联系，这两者在阿尔茨海默病大脑中均有观察到。
