Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
PLoS One. 2011 May 6;6(5):e19264. doi: 10.1371/journal.pone.0019264.
Harmine, a β-carboline alkaloid, is a high affinity inhibitor of the dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) protein. The DYRK1A gene is located within the Down Syndrome Critical Region (DSCR) on chromosome 21. We and others have implicated DYRK1A in the phosphorylation of tau protein on multiple sites associated with tau pathology in Down Syndrome and in Alzheimer's disease (AD). Pharmacological inhibition of this kinase may provide an opportunity to intervene therapeutically to alter the onset or progression of tau pathology in AD. Here we test the ability of harmine, and numerous additional β-carboline compounds, to inhibit the DYRK1A dependent phosphorylation of tau protein on serine 396, serine 262/serine 356 (12E8 epitope), and threonine 231 in cell culture assays and in vitro phosphorylation assays. Results demonstrate that the β-carboline compounds (1) potently reduce the expression of all three phosphorylated forms of tau protein, and (2) inhibit the DYRK1A catalyzed direct phosphorylation of tau protein on serine 396. By assaying several β-carboline compounds, we define certain chemical groups that modulate the affinity of this class of compounds for inhibition of tau phosphorylation.
哈尔明，一种β-咔啉生物碱，是一种高亲和力的双特异性酪氨酸磷酸化调节激酶 1A（DYRK1A）蛋白抑制剂。DYRK1A 基因位于 21 号染色体的唐氏综合征关键区域（DSCR）内。我们和其他人已经暗示 DYRK1A 参与了在唐氏综合征和阿尔茨海默病（AD）中与 tau 病理相关的多个 tau 蛋白丝氨酸位点的磷酸化。该激酶的药理学抑制可能为干预治疗提供机会，以改变 AD 中 tau 病理的发病或进展。在这里，我们测试了哈尔明和许多其他β-咔啉化合物抑制 DYRK1A 依赖性 tau 蛋白丝氨酸 396、丝氨酸 262/丝氨酸 356（12E8 表位）和苏氨酸 231 磷酸化的能力，在细胞培养测定和体外磷酸化测定中。结果表明，β-咔啉化合物（1）强烈降低了三种磷酸化形式的 tau 蛋白的表达，并且（2）抑制了 DYRK1A 催化的 tau 蛋白丝氨酸 396 的直接磷酸化。通过检测几种β-咔啉化合物，我们定义了某些化学基团，这些基团调节了这类化合物抑制 tau 磷酸化的亲和力。
