Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 286, Issue 16, Pages 14639-14648Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.204453
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Funding
- National Institutes of Health [AG027429, AG019158]
- National Natural Science Foundation of China [30973143, 81030059, 30801202]
- Natural Science Foundation of Jiangsu Province, China [BK2009159]
- U.S. Alzheimer's Association [NIRG-08-91126]
- NIA, National Institutes of Health [P30 AG19610]
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Hyperphosphorylation and deposition of tau into neurofibrillary tangles is a hallmark of Alzheimer disease (AD). Alternative splicing of tau exon 10 generates tau isoforms containing three or four microtubule binding repeats (3R-tau and 4R-tau), which are equally expressed in adult human brain. Dysregulation of exon 10 causes neurofibrillary degeneration. Here, we report that cyclic AMP-dependent protein kinase, PKA, phosphorylates splicing factor SRSF1, modulates its binding to tau pre-mRNA, and promotes tau exon 10 inclusion in cultured cells and in vivo in rat brain. PKA-C alpha, but not PKA-C alpha, interacts with SRSF1 and elevates SRSF1-mediated tau exon 10 inclusion. In AD brain, the decreased level of PKA-C alpha correlates with the increased level of 3R-tau. These findings suggest that a down-regulation of PKA dysregulates the alternative splicing of tau exon 10 and contributes to neurofibrillary degeneration in AD by causing an imbalance in 3R-tau and 4R-tau expression.
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