期刊
JOURNAL OF NEUROCHEMISTRY
卷 115, 期 3, 页码 574-584出版社
WILEY
DOI: 10.1111/j.1471-4159.2010.06769.x
关键词
Alzheimer's disease; Dyrk1A; Down syndrome; phosphorylation; Presenilin 1
资金
- Ministry of Education, Science and Technology [20090073210, 2009-0067388]
- Korean government (MOST) [R01-2007-000-11910-0]
- Ministry for Health, Welfare & Family Affairs, Republic of Korea [A092004, A080227]
- Korean Government (MOEHRD) [KRF-2008-314-E00180, KRF-2008-331-E00302]
- Korea Health Promotion Institute [A080227] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Foundation of Korea [2009-0067388, R01-2007-000-11910-0] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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 gamma-secretase complex in the generation of beta-amyloid (A beta), 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 A beta production in mammalian cells and transgenic mice that over-express Dyrk1A. In this study, we describe a potential mechanism by which A beta 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 gamma-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 unphos-phorylated form of PS1. These results reveal a potential regulatory link between Dyrk1A and PS1 in the A beta pathway of DS and AD brains, suggesting that up-regulated Dyrk1A may accelerate AD pathogenesis through PS1 phosphorylation.
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