RGD Reference Report - Increased dosage of Dyrk1A alters alternative splicing factor (ASF)-regulated alternative splicing of tau in Down syndrome. - Rat Genome Database

RGD Reference Report - Increased dosage of Dyrk1A alters alternative splicing factor (ASF)-regulated alternative splicing of tau in Down syndrome. - Rat Genome Database

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Increased dosage of Dyrk1A alters alternative splicing factor (ASF)-regulated alternative splicing of tau in Down syndrome.
Authors:	Shi, Jianhua Zhang, Tianyi Zhou, Chunlei Chohan, Muhammad Omar Gu, Xiaosong Wegiel, Jerzy Zhou, Jianhua Hwang, Yu-Wen Iqbal, Khalid Grundke-Iqbal, Inge Gong, Cheng-Xin Liu, Fei
Citation:	Shi J, etal., J Biol Chem. 2008 Oct 17;283(42):28660-9. doi: 10.1074/jbc.M802645200. Epub 2008 Jul 24.
RGD ID:	401940180
Pubmed:	PMID:18658135 (View Abstract at PubMed)
PMCID:	PMC2568927 (View Article at PubMed Central)
DOI:	DOI:10.1074/jbc.M802645200 (Journal Full-text)
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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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
DYRK1A	Human	Down syndrome		IEP		protein:increased expression:brain (human)	RGD
Dyrk1a	Rat	Down syndrome		ISO	RGD:737237	protein:increased expression:brain (human)	RGD
Dyrk1a	Mouse	Down syndrome		ISO	RGD:737237	protein:increased expression:brain (human)	RGD

Genes (Rattus norvegicus)


Dyrk1a (dual specificity tyrosine phosphorylation regulated kinase 1A)

Genes (Mus musculus)


Dyrk1a (dual-specificity tyrosine phosphorylation regulated kinase 1a)

Genes (Homo sapiens)


DYRK1A (dual specificity tyrosine phosphorylation regulated kinase 1A)