Dyrk1A‐mediated phosphorylation of Presenilin 1: a functional link between Down syndrome and Alzheimer’s disease

Abstract

The dual-specificity tyrosine(Y)-phosphorylation-regulated kinase 1A (Dyrk1A) gene is located on human chromosome 21 and encodes a proline-directed protein kinase that might be responsible for mental retardation and early onset of Alzheimer's disease (AD) in Down syndrome (DS) patients. Presenilin 1 (PS1) is a key component of the c-secretase complex in the generation of b-amyloid (Ab), an important trigger protein in the pathogenesis of AD. Increased Dyrk1A expression has been reported in human AD and DS brains. We previously showed that Dyrk1A increased Ab production in mammalian cells and transgenic mice that over-express Dyrk1A. In this study, we describe a potential mechanism by which Ab is increased in Dyrk1A-over-expressing DS and AD brains. First, we show that PS1 is phosphorylated by the Dyrk1A at Thr 354 and that this phosphorylation increases c-secretase activity. Then, using transgenic mice that over-express human Dyrk1A, we demonstrate that phospho-Thr354-PS1 (pT354-PS1) expression is enhanced when Dyrk1A level is increased. We also show that pT354-PS1 is more stable than the unphosphorylated form of PS1. These results reveal a potential regulatory link between Dyrk1A and PS1 in the Ab pathway of DS and AD brains, suggesting that up-regulated Dyrk1A may accelerate AD pathogenesis through PS1 phosphorylation.

Structural features underlying the selectivity of the kinase inhibitors NBC and dNBC: role of a nitro group that discriminates between CK2 and DYRK1A

“…Given the paucity of selective DYRK1A inhibitors available, with the notable exception of harmine [25], advantage could be taken of dNBC to develop new selective inhibitors of this kinase, which plays important roles in neurodegenerative diseases [37]. For the time being, it should be born in mind that, in addition to DYRK1A, dNBC also drastically inhibits ERK8 and GSK3b, exhibiting an overall promiscuity higher than that of NBC, which is reflected in a Gini coefficient of 0.421 as compared to 0.568 for NBC (see Fig.…”

DYRK1A overexpression decreases plasma lecithin:cholesterol acyltransferase activity and apolipoprotein A-I levels

“…STAT3 phosphorylation is regulated by SHP2, a tyrosine phosphatase activated by tyrosine residue phosphorylation [19]. DYRK1A is located in the DS critical region of HSA21 and belongs to the evolutionarily conserved dual-specificity tyrosine-(Y)-phosphorylation regulated kinase (DYRK) family [20]. Wiechmann et al [21] demonstrated that DYRK1A can phosphorylate Ser727 of STAT3 to increase its activity in COS cells.…”

Recent Advances in the Design, Synthesis, and Biological Evaluation of Selective DYRK1A Inhibitors: A New Avenue for a Disease Modifying Treatment of Alzheimer’s?

“…43 Furthermore, DYRK1A also phosphorylates presenilin 1 (PS1), a subunit of γ-secretase, and this phosphorylation event increases γ-secretase protease activity, further elevating Aβ peptide production. 44 Moreover, research suggests a positive feedback mechanism through which Aβ stimulates the expression of DYRK1A, thereby further accelerating the synthesis of neurotoxic Aβ peptides. 45 These combined observations implicate DYRK1A intimately in the generation of both amyloid and tau pathologies associated with DS and AD and suggest the possibility that efficient pharmacologic inhibition of DYRK1A activity may help to ameliorate simultaneously the production of both pathologies.…”