title: β-carboline compounds, including harmine, inhibit DYRK1A and tau phosphorylation at multiple Alzheimer's disease-related sites.
abstract: 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.
authors.affiliation: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Danielle
authors.initials: D
authors.lastname: Frost
authors.forename: Bessie
authors.initials: B
authors.lastname: Meechoovet
authors.forename: Tong
authors.initials: T
authors.lastname: Wang
authors.forename: Stephen
authors.initials: S
authors.lastname: Gately
authors.forename: Marco
authors.initials: M
authors.lastname: Giorgetti
authors.forename: Irina
authors.initials: I
authors.lastname: Shcherbakova
authors.forename: Travis
authors.initials: T
authors.lastname: Dunckley
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D015153:Blotting, Western; D002243:Carbolines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006247:Harmine / Q000494:pharmacology*; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*; D000097603:Dyrk Kinases
chemical_list: D002243:Carbolines; D006247:Harmine; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D016875:tau Proteins; D000097603:Dyrk Kinases