SR protein 9G8 modulates splicing of tau exon 10 via its proximal downstream intron, a clustering region for frontotemporal dementia mutations
Department of Cell Biology;Shriver Center
Medical Subject Headings
Alternative Splicing; Amino Acid Sequence; Animals; Binding Sites; COS Cells; Cercopithecus aethiops; Cerebral Cortex; Dementia; Exons; Gene Silencing; Hela Cells; Humans; Introns; Nucleocytoplasmic Transport Proteins; Point Mutation; RNA Interference; RNA-Binding Proteins; tau Proteins
The microtubule-associated protein tau is important to normal neuronal function in the mammalian nervous system. Aggregated tau is the major component of neurofibrillary tangles (NFTs), present in several neurodegenerative diseases, including Alzheimer's and frontotemporal dementia with Parkinsonism (FTDP). Splicing misregulation of adult-specific exon 10 results in expression of abnormal ratios of tau isoforms, leading to FTDP. Positions +3 to +16 of the intron downstream of exon 10 define a clustering region for point mutations that are found in FTDP. The serine/arginine-rich (SR) factor 9G8 strongly inhibits inclusion of tau exon 10. In this study, we established that 9G8 binds directly to this clustering region, requires a wild-type residue at position +14 to inhibit exon inclusion, and RNAi constructs against 9G8 increase exon 10 inclusion. These results indicate that 9G8 plays a key role in regulation of exon 10 splicing and imply a pathogenic role in neurodegenerative diseases.
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Citation: Mol Cell Neurosci. 2007 Jan;34(1):48-58. Epub 2006 Nov 29. Link to article on publisher's site