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Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome
Author(s) -
Liu Fei,
Liang Zhihou,
Wegiel Jerzy,
Hwang YuWen,
Iqbal Khalid,
GrundkeIqbal Inge,
Ramakrishrayan,
Gong ChengXin
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.07-104539
Subject(s) - dyrk1a , phosphorylation , gsk 3 , kinase , chemistry , glycogen synthase , down syndrome , gsk3b , microbiology and biotechnology , tyrosine phosphorylation , trisomy , biology , genetics
Adults with Down syndrome (DS) develop Alzheimer neurofibrillary degeneration in the brain, but the underlying molecular mechanism is unknown. Here, we report that the presence of an extra copy of the dual‐specificity tyrosine‐phosphorylated and regulated kinase 1A ( Dyrk1A ) gene due to trisomy 21 resulted in overexpression of Dyrk1A and elevated kinase activity in DS brain. Dyrk1A phosphorylated tau at several sites, and these sites were hyperphosphory‐lated in adult DS brains. Phosphorylation of tau by Dyrk1A primed its further phosphorylation by glycogen synthase kinase‐3β (GSK‐3β). Dyrk1A‐induced tau phosphorylation inhibited tau's biological activity and promoted its self‐aggregation. In Ts65Dn mouse brain, an extra copy of the Dyrk1A gene caused increased expression and activity of Dyrk1A and resulted in increased tau phosphorylation. These findings strongly suggest a novel mechanism by which the overexpression of Dyrk1A in DS brain causes neurofibrillary degeneration via hyperphosphorylating tau. Liu, F., Liang, Z., Wegiel, J., Hwang, Y.‐W., Iqbal, K., Grundke‐Iqbal, I., Ramakrishna, N., Gong, C.‐X. Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome. FASEB J. 22, 3224–3233 (2008)