Dyrk1A overexpression in immortalized hippocampal cells produces the neuropathological features of Down syndrome

Joongkyu Park; Eun Jin Yang; Joo Heon Yoon; Kwang Chul Chung

doi:10.1016/j.mcn.2007.07.007

Dyrk1A overexpression in immortalized hippocampal cells produces the neuropathological features of Down syndrome

Joongkyu Park, Eun Jin Yang, Joo Heon Yoon, Kwang Chul Chung

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Abstract

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.

Original language	English
Pages (from-to)	270-279
Number of pages	10
Journal	Molecular and Cellular Neuroscience
Volume	36
Issue number	2
DOIs	https://doi.org/10.1016/j.mcn.2007.07.007
Publication status	Published - 2007 Oct

Bibliographical note

Funding 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

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10.1016/j.mcn.2007.07.007

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@article{38a6c58635b64264ad99a5431edbe356,

title = "Dyrk1A overexpression in immortalized hippocampal cells produces the neuropathological features of Down syndrome",

abstract = "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.",

author = "Joongkyu Park and Yang, {Eun Jin} and Yoon, {Joo Heon} and Chung, {Kwang Chul}",

note = "Funding 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.).",

year = "2007",

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language = "English",

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AU - Park, Joongkyu

AU - Yang, Eun Jin

AU - Yoon, Joo Heon

AU - Chung, Kwang Chul

N1 - Funding 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.).

PY - 2007/10

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N2 - 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.

AB - 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.

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Dyrk1A overexpression in immortalized hippocampal cells produces the neuropathological features of Down syndrome

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

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