Down syndrome (DS) is the most common genetic disorder, characterized by mental retardation, congenital heart abnormalities, and susceptibility to Alzheimer's disease (AD). Brain development of DS patients is associated with elevated apoptosis and abnormal neuronal differentiation. Those key features are closely associated with many genes mapped within Down syndrome critical region (DSCR) on human chromosome 21. Proline-directed serine/threonine kinase, Dyrk1A, is mapped within DSCR, and involved in the control of cell growth and postembryonic neurogenesis. Despite the potential involvement of Dyrk1A in neurodegeneration, its links to AD susceptibility and the neuropathology of DS patients are not yet clearly understood. Here, we report evidence supporting the correlation between Dyrk1A and neuropathology of DS. Our results show that Dyrk1A interacts with and directly phosphorylates tau and amyloid precursor protein in immortalized hippocampal progenitor H19-7 cells. In addition, the formation of tau inclusion and the enhanced generation of β-amyloid fragment were detected in H19-7 cells that overexpressed Dyrk1A. Furthermore, these cells show a marked increase in apoptotic cell death under conditions of serum deprivation and also exhibit defects in neuronal differentiation. These results suggest that up-regulation of Dyrk1A may cause AD-like pathogenesis and abnormal neurobiological features in DS patients.
Bibliographical noteFunding Information:
We are deeply grateful to W. Becker, L. Petrucelli, Y.H. Suh, and K.F. Lau for generously providing cDNA constructs. This study was supported by a grant from the Brain Research Center of the 21st Century Frontier Research Program funded by the Ministry of Science and Technology (M103KV010011-06K2201-01110 to K.C.C.), by Basic Research Grant from the Korea Science and Engineering Foundation (KOSEF; R01-2004-000-10673-0 to K.C.C.), and by grants from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A050181 and A060440 to K.C.C.). This work was also supported by KOSEF through the National Research Lab. Program fund (R04-2007-00020014-0 to K.C.C.), partly supported by the Korea Research Foundation Grant (KRF-2004-005-E0017), the Brain Korea 21 Projects from Korea Research Foundation (to J.P.), and supported in part by Seoul Science Fellowship Program from Seoul Metropolitan Government (to J.P.).
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cellular and Molecular Neuroscience
- Cell Biology