An SRp75/hnRNPG complex interacting with hnRNPE2 regulates the 5' splice site of tau exon 10, whose misregulation causes frontotemporal dementia

Yan Wang, Junning Wang, Lei Gao, Stefan Stamm, Athena Andreadis

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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.

Original languageEnglish
Pages (from-to)130-138
Number of pages9
JournalGene
Volume485
Issue number2
DOIs
StatePublished - Oct 10 2011

Bibliographical note

Funding Information:
This work was supported by NIH grants R01 AG18486 to A. A. and R21 HD056195 to A. A. and S. S. We want to thank Dr. Alonso Ross for his generous subsidy of the shRNA clones via the UMMS SiRNA Core.

Keywords

  • Alternative splicing regulation
  • Exon 10 and tangle dementia
  • Heterogeneous nuclear ribonucleoproteins g and e2
  • Isoform ratios
  • MAP tau
  • Splicing factor srP75

ASJC Scopus subject areas

  • Genetics

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