title: Link between DYRK1A overexpression and several-fold enhancement of neurofibrillary degeneration with 3-repeat tau protein in Down syndrome.
abstract: Triplication of chromosome 21 in Down syndrome (DS) results in overexpression of the minibrain kinase/dual-specificity tyrosine phosphorylated and regulated kinase 1A gene (DYRK1A). DYRK1A phosphorylates cytoplasmic tau protein and appears in intraneuronal neurofibrillary tangles (NFTs). We have previously shown significantly more DYRK1A-positive NFTs in DS brains than in sporadic Alzheimer disease (AD) brains. This study demonstrates a gene dosage-proportional increase in the level of DYRK1A in DS in the cytoplasm and the cell nucleus, and enhanced cytoplasmic and nuclear immunoreactivity of DYRK1A in DS. The results suggest that overexpressed DYRK1A may alter both phosphorylation of tau and alternative splicing factor (ASF). Two-dimensional electrophoresis revealed modification of ASF phosphorylation in DS/AD and AD in comparison to controls. Altered phosphorylation of ASF by overexpressed nuclear DYRK1A may contribute to the alternative splicing of the tau gene and an increase by 2.68 × of the 3R/4R ratio in DS/AD, and a several-fold increase in the number of 3R tau-positive NFTs in DS/AD subjects compared with that in sporadic AD subjects. These data support the hypothesis that phosphorylation of ASF by overexpressed DYRK1A may contribute to alternative splicing of exon 10, increased expression of 3R tau, and early onset of neurofibrillary degeneration in DS.
authors.affiliation: Department of Developmental Neurobiology, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, USA. Jerzy.Wegiel@omr.state.ny.us
authors.forename: Jerzy
authors.initials: J
authors.lastname: Wegiel
authors.forename: Wojciech
authors.initials: W
authors.lastname: Kaczmarski
authors.forename: Madhabi
authors.initials: M
authors.lastname: Barua
authors.forename: Izabela
authors.initials: I
authors.lastname: Kuchna
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Nowicki
authors.forename: Kuo-Chiang
authors.initials: KC
authors.lastname: Wang
authors.forename: Jarek
authors.initials: J
authors.lastname: Wegiel
authors.forename: Shuang Ma
authors.initials: SM
authors.lastname: Yang
authors.forename: Janusz
authors.initials: J
authors.lastname: Frackowiak
authors.forename: Bozena
authors.initials: B
authors.lastname: Mazur-Kolecka
authors.forename: Wayne P
authors.initials: WP
authors.lastname: Silverman
authors.forename: Barry
authors.initials: B
authors.lastname: Reisberg
authors.forename: Isabel
authors.initials: I
authors.lastname: Monteiro
authors.forename: Mony
authors.initials: M
authors.lastname: de Leon
authors.forename: Thomas
authors.initials: T
authors.lastname: Wisniewski
authors.forename: Arthur
authors.initials: A
authors.lastname: Dalton
authors.forename: Florence
authors.initials: F
authors.lastname: Lai
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Hwang
authors.forename: Tatyana
authors.initials: T
authors.lastname: Adayev
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.forename: Khalid
authors.initials: K
authors.lastname: Iqbal
authors.forename: Inge-Grundke
authors.initials: IG
authors.lastname: Iqbal
authors.forename: Cheng-Xin
authors.initials: CX
authors.lastname: Gong
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002417:Cattle; D004314:Down Syndrome / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009410:Nerve Degeneration / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D016874:Neurofibrillary Tangles / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats; D018911:Trinucleotide Repeats / Q000235:genetics; D016875:tau Proteins / Q000096:biosynthesis / Q000235:genetics*; D000097603:Dyrk Kinases
chemical_list: D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D016875:tau Proteins; D000097603:Dyrk Kinases