DYRK1A-mediated hyperphosphorylation of Tau. A functional link between Down syndrome and Alzheimer disease.
Most individuals with Down syndrome show early onset of Alzheimer disease (AD), resulting from the extra copy of chromosome 21. Located on this chromosome is a gene that encodes the dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). One of the pathological hallmarks in AD is the presence of neurofibrillary tangles (NFTs), which are insoluble deposits that consist of abnormally hyperphosphorylated Tau. Previously it was reported that Tau at the Thr-212 residue was phosphorylated by Dyrk1A in vitro. To determine the physiological significance of this phosphorylation, an analysis was made of the amount of phospho-Thr-212-Tau (pT212) in the brains of transgenic mice that overexpress the human DYRK1A protein (DYRK1A TG mice) that we recently generated. A significant increase in the amount of pT212 was found in the brains of DYRK1A transgenic mice when compared with age-matched littermate controls. We further examined whether Dyrk1A phosphorylates other Tau residues that are implicated in NFTs. We found that Dyrk1A also phosphorylates Tau at Ser-202 and Ser-404 in vitro. Phosphorylation by Dyrk1A strongly inhibited the ability of Tau to promote microtubule assembly. Following this, using mammalian cells and DYRK1A TG mouse brains, it was demonstrated that the amounts of phospho-Ser-202-Tau and phospho-Ser-404-Tau are enhanced when DYRK1A amounts are high. These results provide the first in vivo evidence for a physiological role of DYRK1A in the hyperphosphorylation of Tau and suggest that the extra copy of the DYRK1A gene contributes to the early onset of AD.
Ryoo
Soo-Ryoon
SR
Graduate Program in Neuroscience, Institute for Brain Science and Technology, Inje University, Busan 614-735, South Korea.
Jeong
Hey Kyeong
HK
Radnaabazar
Chinzorig
C
Yoo
Jin-Ju
JJ
Cho
Hyun-Jeong
HJ
Lee
Hye-Won
HW
Kim
In-Sook
IS
Cheon
Young-Hee
YH
Ahn
Young Soo
YS
Chung
Sul-Hee
SH
Song
Woo-Joo
WJ
D000544:Alzheimer Disease / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism; D004314:Down Syndrome / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry; D012694:Serine / Q000737:chemistry; D013912:Threonine / Q000737:chemistry; D016875:tau Proteins / Q000737:chemistry*; D000097603:Dyrk Kinases
D018076:DNA, Complementary; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011994:Recombinant Proteins; D012694:Serine; D013912:Threonine; D016875:tau Proteins; D000097603:Dyrk Kinases