S1-03-05: Increased dosage of Dyrk1A alters the alternative splicing of Tau exon 10 in Down syndrome

Abstract

Tau is a major neuronal microtubule-associated protein. Adult human brain expresses six isoforms of tau coded by a single gene and generated by alternative splicing of exon 2, 3 and 10. Inclusion and exclusion of tau exon 10 result in 4R-tau and 3R-tau, respectively. In normal adult human brain, equal amounts of 3R-tau and 4R-tau are expressed. Disruption of the physiological balance between these groups due to certain tau mutations causes frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), which is characterized by neurofibrillary degeneration of abnormally hyperphosphorylated tau. Individuals with Down syndrome (DS) develop Alzhiemer-type tau pathology at much younger age than those with AD, but the molecular basis of this alteration is not fully understood. In present study, we measured the levels of total tau, 3R-tau, and 4R-tau in DS brain tissues by immunoblots and studied the regulation of Dyrk1A, a kinase encoded by a gene in the DS critical region, on alternative splicing of tau exon 10 by using mini-tau gene pCI/SI9/LI10, consisting of tau exons 9–11, part of intron 9 (SI9) and the full length of intron 10 (LI10) in cultured cells. We found that alternative splicing factor (ASF) regulated alternative splicing of tau exon 10 very efficiently. Dyrk1A phosphorylates ASF at Ser227, Ser234 and Ser238, driving it from nascent transcripts into nuclear speckles and preventing it from facilitating tau exon 10 inclusion. The increased dosage of Dyrk1A in DS is directly related to an increase in 3R-tau level and 3R-tau-positive neurofibrillary tangles. These findings suggest that, in addition to phosphorylation of tau, overexpression of Dyrk1A in DS brain leads to dysregulation of tau exon 10 alternative splicing and increase in 3R-tau/4R-tau ratio, which may initiate and accelerate abnormal hyperphosphorylation of tau and neurofibrillary degeneration. Imbalance in the levels of 3R-tau and 4R-tau in DS brain by Dyrk1A-induced dysregulation of tau alternative splicing represents a novel mechanism of neurofibrillary degeneration and may help explain the early-onset tauopathy in individuals with DS.