An SRp75/hnRNPG complex interacting with hnRNPE2 regulates the 5' splice site of tau exon 10, whose misregulation causes frontotemporal dementia |
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Authors: | Wang Yan Wang Junning Gao Lei Stamm Stefan Andreadis Athena |
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Affiliation: | a Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USAb Shriver Center at University of Massachusetts Medical School, Waltham, Massachusetts 02452, USAc Department of Biochemistry, University of Kentucky, Lexington, Kentucky 40536, USA |
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Abstract: | Tau is a neuronal-specific microtubule-associated protein that plays an important role in establishing neuronal polarity and maintaining the axonal cytoskeleton. Aggregated tau is the major component of neurofibrillary tangles (NFTs), structures present in the brains of people affected by neurodegenerative diseases called tauopathies. Tauopathies include Alzheimer's disease (AD), frontotemporal dementia with Parkinsonism (FTDP-17), the early onset dementia observed in Down syndrome (DS; trisomy 21) and the dementia component of myotonic dystrophy type 1 (DM1). Splicing misregulation of adult-specific exon 10, which codes for a microtubule binding domain, results in expression of abnormal ratios of tau isoforms, leading to FTDP-17. Positions 3 to 19 of the intron downstream of exon 10 define a hotspot of splicing regulation: the region diverges between humans and rodents, and point mutations within it result in tauopathies. In this study, we investigated three regulators of exon 10 splicing: serine/arginine-rich protein SRp75 and heterogeneous nuclear ribonucleoproteins hnRNPG and hnRNPE2. SRp75 and hnRNPG inhibit splicing of exon 10 whereas hnRNPE2 activates it. Using co-transfections, co-immunoprecipitations and RNAi we discovered that SRp75 binds to the proximal downstream intron of tau exon 10 at the FTDP-17 hotspot region; and that hnRNPG and hnRNPE2 interact with SRp75. Thus, increased exon 10 inclusion in FTDP mutants may arise from weakened SRp75 binding. This work provides insights into the splicing regulation of the tau gene and into possible strategies for correcting the imbalance in tauopathies caused by changes in the ratio of exon 10. |
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Keywords: | AD, Alzheimer's disease DM1, myotonic dystrophy type 1 DS, Down syndrome (k)bp, (kilo)base pairs FTDP-17, frontotemporal dementia with Parkinsonism hnRNP, heterogeneous nuclear ribonucleoprotein IP, immunoprecipitation ISS, intronic splicing silencer MAP, microtubule-associated protein nt, nucleotides NFT, neurofibrillary tangle RRM, RNA recognition motif R/S, arginine/serine snRNPs, small nuclear ribonucleoproteins SR proteins, serine/arginine-rich proteins |
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