β-carboline compounds, including Harmine, inhibit DYRK1A and Tau phosphorylation at multiple Alzheimer's disease-related sites

Danielle Frost, Bessie Meechoovet, Tong Wang, Stephen Gately, Marco Giorgetti, Irina Shcherbakova, Travis Dunckley

Research output: Contribution to journalArticle

82 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere19264
JournalPLoS One
Volume6
Issue number5
DOIs
StatePublished - May 16 2011
Externally publishedYes

Fingerprint

Harmine
Carbolines
Phosphorylation
Alzheimer disease
tau Proteins
phosphorylation
Alzheimer Disease
Serine
serine
Down syndrome
Pathology
Assays
proteins
phosphotransferases (kinases)
Chromosomes, Human, Pair 21
Aptitude
Threonine
Chromosomes
Down Syndrome
Cell culture

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

β-carboline compounds, including Harmine, inhibit DYRK1A and Tau phosphorylation at multiple Alzheimer's disease-related sites. / Frost, Danielle; Meechoovet, Bessie; Wang, Tong; Gately, Stephen; Giorgetti, Marco; Shcherbakova, Irina; Dunckley, Travis.

In: PLoS One, Vol. 6, No. 5, e19264, 16.05.2011.

Research output: Contribution to journalArticle

Frost, Danielle ; Meechoovet, Bessie ; Wang, Tong ; Gately, Stephen ; Giorgetti, Marco ; Shcherbakova, Irina ; Dunckley, Travis. / β-carboline compounds, including Harmine, inhibit DYRK1A and Tau phosphorylation at multiple Alzheimer's disease-related sites. In: PLoS One. 2011 ; Vol. 6, No. 5.
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