Abstract
Alternative splicing of tau exon 10 generates tau isoforms with three or four microtubule-binding repeats, 3R-tau and 4R-tau, which is equally expressed in adult human brain. Imbalanced expression in 3R-tau and 4R-tau has been found in several sporadic and inherited tauopathies, suggesting that dysregulation of tau exon 10 is sufficient to cause neurodegenerative diseases. We previously reported that Dyrk1A, which is overexpressed in Down syndrome brains, regulates alternative splicing of exogenous tau exon 10. In the present study, we investigated the regulation of endogenous tau exon 10 splicing by Dyrk1A. We found that inhibition of Dyrk1A enhanced tau exon 10 inclusion, leading to an increase in 4R-tau/3R-tau ratio in differentiated-human neuronal progenitors and in the neonatal rat brains. Accompanied with overexpression of Dyrk1A, 3R-tau was increased and 4R-tau was decreased in the neonatal brains of Ts65Dn mice, a model of Down syndrome. Treatment with Dyrk1A inhibitor, green tea flavonol epigallocatechin-gallate (EGCG), from gestation to adulthood suppressed 3R-tau expression and rescued anxiety and memory deficits in Ts65Dn mouse brains. Thus, Dyrk1A might be an ideal therapeutic target for Alzheimer’s disease, especially for Down syndrome and EGCG which inhibits Dyrk1A may have potential effect on the treatment or prevention of this disease.
Highlights
Tau is the major neuronal microtubule associated protein and plays a crucial role in the maintenance of both the neuronal cytoskeleton and axonal transport
We recently found that Dyrk1A phosphorylates splicing factors, alternative splicing factor/splicing factor 2 (SF2/ASF), 9G8, SC35, and SRp55, and modulates their function in the regulation of tau exon 10 inclusion in vitro[17,18,19]
In addition to the inherited frontal lobe dementia, imbalanced expression of 3R-tau and 4R-tau has been seen in sporadic tauopathies
Summary
Tau is the major neuronal microtubule associated protein and plays a crucial role in the maintenance of both the neuronal cytoskeleton and axonal transport. Adult human brain expresses six isoforms of tau from a single gene by alternative splicing of the exons 2, 3 and 10 of its pre-mRNA6–8. Many mutations in tau gene associated with frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) cause dysregulation of tau exon 10 splicing but not protein sequence, leading to a selective increase in either 3R- or 4R-tau[10]. We recently found that Dyrk1A phosphorylates splicing factors, alternative splicing factor/splicing factor 2 (SF2/ASF), 9G8, SC35, and SRp55, and modulates their function in the regulation of tau exon 10 inclusion in vitro[17,18,19]. Whether Dyrk1A overexpression causes changes in 3R-tau and 4R-tau resulting from endogenous tau exon 10 splicing in vivo is not determined
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