Abstract
Mutations in the human tau gene leading to aberrant splicing have been identified in FTDP-17, an autosomal dominant hereditary neurodegenerative disorder. Molecular mechanisms by which such mutations cause tau aberrant splicing were not understood. We characterized two mutations in exon 10 of the tau gene, N279K and Del280K. Our results revealed an exonic splicing enhancer element located in exon 10. The activity of this AG-rich splicing enhancer was altered by N279K and Del280K mutations. This exonic enhancer element interacts with human Tra2 beta protein. The interaction between Tra2 beta and the exonic splicing enhancer correlates with the activity of this enhancer element in stimulating splicing. Biochemical studies including in vitro splicing and RNA interference experiments in transfected cells support a role for Tra2 beta protein in regulating alternative splicing of human tau gene. Our results implicate the human tau gene as a target gene for the alternative splicing regulator Tra2 beta, suggesting that Tra2 beta may play a role in aberrant tau exon 10 alternative splicing and in the pathogenesis of tauopathies.
Highlights
Microtubule-associated protein tau plays an important role in microtubule assembly and stabilization [1,2,3,4,5,6,7,8,9]
The level of expression of SRp40 was comparable with that of transformer 2 (Tra2) in the lysates of transfected cells. These results demonstrate that Tra2 could interact with the AG-rich element inside exon 10 and that mutations found in FTDP-17 patients affect the binding of Tra2 to this element
We report characterization of an exonic splicing enhancer located in exon 10 of the human tau gene with AATAAGAAG as the wild-type sequence
Summary
In addition to intronic mutations, several exonic mutations (shown in Fig. 1), including N279K, Del280K, L284L, N296N, N296H, and S305N, have been found to alter exon 10 splicing [20, 26, 27, 30, 37] It was proposed based on sequence analyses and RT-PCR studies that these mutations may change the activity of certain exonic regulatory elements in exon 10, the mechanism by which these mutations affect exon 10 splicing was not clear. Our results have revealed an exonic splicing enhancer element located in exon 10 The activity of this AG-rich splicing enhancer is affected by N279K and Del280K mutations. Down-regulation of Tra2 expression by RNA interference in transfected cells led to a reduction in tau exon 10 inclusion. These observations suggest that human Tra2 may act as an important regulator for facilitating exon 10 inclusion in tau splicing
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