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J. Biol. Chem., Vol. 282, Issue 48, 34850-34857, November 30, 2007

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DYRK1A-mediated Hyperphosphorylation of Tau

A FUNCTIONAL LINK BETWEEN DOWN SYNDROME AND ALZHEIMER DISEASE^*

Soo-Ryoon Ryoo, Hey Kyeong Jeong, Chinzorig Radnaabazar, Jin-Ju Yoo, Hyun-Jeong Cho, Hye-Won Lee, In-Sook Kim, Young-Hee Cheon^¶, Young Soo Ahn, Sul-Hee Chung¹, and Woo-Joo Song²

From the Graduate Program in Neuroscience, Institute for Brain Science and Technology, Inje University, Busan 614-735, South Korea, Brain Korea 21 Project for Medical Science, Brain Research Institute and Department of Pharmacology, Yonsei University College of Medicine, Seoul 120-749, South Korea, and the ^¶Department of Anatomy and Neurosciences, Eulji University School of Medicine, Daejeon 301-832, South Korea

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.

Received for publication, September 3, 2007 , and in revised form, September 26, 2007.

^* This work was supported by KOSEF Grant R01-2007-000-11910-0 and BRC Grant M103KV010022-06K2201-02210 (to S.-H. C.) funded by the Korean Government (MOST), by Korea Research Foundation Grants KRF-2006-331-C00189 (to W.-J. S.) and KRF-2006-331-E00288 (to S.-H. C.) funded by the Korean Government (MOEHRD), and by the Institute for Brain Science and Technology Grant 2006. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: Graduate Program in Neuroscience, Institute for Brain Science and Technology, Inje University, 633-146 Gaegeum-2-Dong, Busanjin-Gu, Busan 614-735, South Korea. Tel.: 82-51-892-4185; Fax: 82-51-892-0059; E-mail: sulchung{at}inje.ac.kr. ² To whom correspondence may be addressed. Tel.: 82-51-892-4186; Fax: 82-51-892-0059; E-mail: wjsong{at}inje.ac.kr.

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