title: An SRp75/hnRNPG complex interacting with hnRNPE2 regulates the 5' splice site of tau exon 10, whose misregulation causes frontotemporal dementia.
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.
authors: Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
authors: Yan
authors: Y
authors: Wang
authors: Junning
authors: J
authors: Wang
authors: Lei
authors: L
authors: Gao
authors: Stefan
authors: S
authors: Stamm
authors: Athena
authors: A
authors: Andreadis
mesh_terms: D017398:Alternative Splicing; D000544:Alzheimer Disease / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism / Q000473:pathology; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005091:Exons; D057180:Frontotemporal Dementia / Q000235:genetics*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D007438:Introns; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D020734:Parkinsonian Disorders / Q000235:genetics; D022821:RNA Splice Sites; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D000068103:Serine-Arginine Splicing Factors; D024801:Tauopathies / Q000235:genetics; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D034441:Heterogeneous-Nuclear Ribonucleoproteins; D022821:RNA Splice Sites; D016601:RNA-Binding Proteins; C081934:SRSF4 protein, human; D016875:tau Proteins; D000068103:Serine-Arginine Splicing Factors