| Increased dosage of Dyrk1A alters alternative splicing factor (ASF)-regulated alternative splicing of tau in Down syndrome. | |
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MedLine Citation:
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PMID: 18658135 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Two groups of tau, 3R- and 4R-tau, are generated by alternative splicing of tau exon 10. Normal adult human brain expresses equal levels of them. Disruption of the physiological balance is a common feature of several tauopathies. Very early in their life, individuals with Down syndrome (DS) develop Alzheimer-type tau pathology, the molecular basis for which is not fully understood. Here, we demonstrate that Dyrk1A, a kinase encoded by a gene in the DS critical region, phosphorylates alternative splicing factor (ASF) at Ser-227, Ser-234, and Ser-238, driving it into nuclear speckles and preventing it from facilitating tau exon 10 inclusion. The increased dosage of Dyrk1A in DS brain due to trisomy of chromosome 21 correlates to an increase in 3R-tau level, which on abnormal hyperphosphorylation and aggregation of tau results in neurofibrillary degeneration. Imbalance of 3R- and 4R-tau in DS brain by Dyrk1A-induced dysregulation of alternative splicing factor-mediated alternative splicing of tau exon 10 represents a novel mechanism of neurofibrillary degeneration and may help explain early onset tauopathy in individuals with DS. |
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Authors:
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Jianhua Shi; Tianyi Zhang; Chunlei Zhou; Muhammad Omar Chohan; Xiaosong Gu; Jerzy Wegiel; Jianhua Zhou; Yu-Wen Hwang; Khalid Iqbal; Inge Grundke-Iqbal; Cheng-Xin Gong; Fei Liu |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2008-07-24 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 283 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2008 Oct |
Date Detail:
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Created Date: 2008-10-13 Completed Date: 2008-11-25 Revised Date: 2011-09-26 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 28660-9 Citation Subset: IM |
Affiliation:
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Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, P. R. China. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Alternative Splicing Animals Brain / embryology, metabolism COS Cells Cell Line, Tumor Cercopithecus aethiops Down Syndrome / metabolism* Hela Cells Humans Models, Biological Neurodegenerative Diseases / pathology Protein-Serine-Threonine Kinases / metabolism* Protein-Tyrosine Kinases / metabolism* Rats Serine / chemistry tau Proteins / chemistry* |
| Grant Support | |
ID/Acronym/Agency:
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AG019158/AG/NIA NIH HHS; AG027429/AG/NIA NIH HHS; HD43960/HD/NICHD NIH HHS; R01 AG019158-08/AG/NIA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/MAPT protein, human; 0/tau Proteins; 56-45-1/Serine; EC 2.7.1.-/Dyrk kinase; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.11.1/Protein-Serine-Threonine Kinases |
| Comments/Corrections | |
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