Determinants of 4-Repeat Tau Expression

D’Souza, Ian; Schellenberg, Gerard D.

doi:10.1074/jbc.m909470199

Cited by 122 publications

(49 citation statements)

References 34 publications

(24 reference statements)

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“…Of the three factors, SRp30c binds strongly (ϳ10ϫ compared with the control vector), SRp55 binds moderately (ϳ5ϫ), and htra2␤1 binds weakly (ϳ2.5ϫ). The relative binding strength of htra2␤1 is consistent with results from other laboratories (32,33). SRp55 binds weakly to the E10-⌬3/4 deletion, and SRp30c does not bind at all to it (Fig.…”

Section: Domains Of Splicing Factors Required For Regulating the Splisupporting

confidence: 79%

“…Using directed mutagenesis, as previously described (27,30), we created nine deletions that scan exon 2 in SP/2L (E2-⌬1 to E2-⌬9; Fig. 1A) and three deletions and a double point mutation in exon 10 (E10-⌬2/3/4, E10-⌬8/9, and E10-⌬15, following the nomenclature of D'Souza and Schellenberg (32), and point mutation M280 in the M3 background (Fig. 1C) (24)).…”

Section: Methodsmentioning

confidence: 99%

“…9A, we show an updated model of exon 2 splicing regulation that incorporates this new knowledge. (25,27,(31)(32)(33)(34) showed that tau exon 10 contains several silencers. Mutations in them appear in FTDP pedigrees: N279K, L284L, and N296N, which occur within E10-⌬2/3/4, E10-⌬8/9, and E10-⌬15, respectively (Fig.…”

Section: One Of the Regulatory Elements Of Tau Exon 2 Is An Exonic Simentioning

confidence: 99%

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Tau Exons 2 and 10, Which Are Misregulated in Neurodegenerative Diseases, Are Partly Regulated by Silencers Which Bind a SRp30c·SRp55 Complex That Either Recruits or Antagonizes htra2β1

Wang

Gao

et al. 2005

Journal of Biological Chemistry

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Tau is a microtubule-associated protein whose transcript undergoes complex regulated splicing in the mammalian nervous system. Exon 2 modulates the tau N-terminal domain, which interacts with the axonal membrane. Exon 10 codes for a microtubule binding domain, increasing the affinity of tau for microtubules. Both exons are excluded from fetal brain, but their default behavior is inclusion, suggesting that silencers are involved in their regulation. Exon 2 is significantly reduced in myotonic dystrophy type 1, whose symptoms include dementia. Mutations that affect exon 10 splicing cause frontotemporal dementia (FTDP). In this study, we investigated three regulators of exon 2 and 10 splicing: serine/arginine-rich (SR) proteins SRp55, SRp30c, and htra2␤1. The first two inhibit both exons; htra2␤1 inhibits exon 2 but activates exon 10. By deletion analysis, we identified splicing silencers located at the 5 end of each exon. Furthermore, we demonstrated that SRp30c and SRp55 bind to both silencers and to each other. In exon 2, htra2␤1 binds to the inhibitory heterodimer through its RS1 domain but not to exon 2, whereas in exon 10 the heterodimer may sterically interfere with htra2␤1 binding to a purine-rich enhancer (defined by FTDP mutation E10-⌬5 ‫؍‬ ⌬280K) directly downstream of the silencer. Increased exon 10 inclusion in FTDP mutant ENH (N279K) may arise from abolishing SRp30c binding. Also, htra2␤3, a naturally occurring variant of htra2␤1, no longer inhibits exon 2 splicing but can partially rescue splicing of exon 10 in FTDP mutation E10-⌬5. This work provides interesting insights into the splicing regulation of the tau gene.Alternative splicing is a versatile and widespread mechanism for generating multiple mRNAs from a single transcript (1, 2). Splicing choices are spatially and temporally regulated, and the ensuing mRNAs produce functionally diverse proteins, contributing significantly to proteomic complexity (2, 3).Splicing is carried out by the spliceosome, a large and dynamic complex of proteins and small RNAs (4, 5). A major question in splicing, and an obvious point of regulation, is how the spliceosome recognizes authentic splicing sites. The rules governing splice site selection are not fully understood; combinatorial control and "weighing" of splice element strength are used to enable precise recognition of the short and degenerate splice sites (6). Despite the high fidelity of exon recognition in vivo, it is currently impossible to accurately predict alternative exons (7). Exonic and intronic enhancers and silencers are involved in splicing regulation (8, 9). Their mutation can result in human disease by causing aberrant splicing (10, 11).On the trans side of regulation, mammalian splicing regulators mostly belong to two superfamilies, the serine/argininerich (SR) 1 proteins and the heterogeneous ribonuclear proteins (hnRNPs), neither of which is exclusively involved in alternative splicing (12, 13). The former are also components of the spliceosome, whereas the latter are also involved in pre-mRN...

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Section: Domains Of Splicing Factors Required For Regulating the Splisupporting

confidence: 79%

Section: Methodsmentioning

confidence: 99%

Section: One Of the Regulatory Elements Of Tau Exon 2 Is An Exonic Simentioning

confidence: 99%

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Tau Exons 2 and 10, Which Are Misregulated in Neurodegenerative Diseases, Are Partly Regulated by Silencers Which Bind a SRp30c·SRp55 Complex That Either Recruits or Antagonizes htra2β1

Wang

Gao

et al. 2005

Journal of Biological Chemistry

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“…Thus, alteration in the tau 4R/tau 3R proportion of isoforms is sufficient to trigger neurodegeneration in frontotemporal dementia, and probably, this might also play a role in other neurodegenerative disorders such as progressive nuclear palsy or corticobasal degeneration, which are characterized by an increase in tau 4R isoforms (11). Thus, gaining insight to the regulation of alternative splicing of human tau exon 10 has been of critical interest (15,22).…”

mentioning

confidence: 99%

“…Most exonic mutations are single amino acid substitutions that result in the reduced ability of tau to interact with microtubules (8,9). On the other hand, some exonic and virtually all the intronic FTDP-17 tau mutations affect RNA processing, resulting in an increase in tau 4R isoforms (8,(12)(13)(14)(15)(16)(17)(18)(19)(20) with the only exception being the exonic A280K mutation that results in a decrease in tau 4R isoforms (15)(16)(17)(18)(19)(20)(21). Thus, alteration in the tau 4R/tau 3R proportion of isoforms is sufficient to trigger neurodegeneration in frontotemporal dementia, and probably, this might also play a role in other neurodegenerative disorders such as progressive nuclear palsy or corticobasal degeneration, which are characterized by an increase in tau 4R isoforms (11).…”

mentioning

confidence: 99%

Glycogen Synthase Kinase-3 Plays a Crucial Role in Tau Exon 10 Splicing and Intranuclear Distribution of SC35

Hernández

Pérez

Lucas

et al. 2004

Journal of Biological Chemistry

128

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Tauopathies, including Alzheimer's disease, are neurodegenerative disorders in which tau protein accumulates as a consequence of alterations in its metabolism. At least three different types of alterations have been described; in some cases, an aberrant mRNA splicing of tau exon 10 occurs; in other cases, the disorder is a consequence of missense mutations and, in most cases, aberrant tau hyperphosphorylation takes place. Glycogen synthase kinase-3 (GSK-3) has emerged as a key kinase that is able to interact with several proteins involved in the ethiology of Alzheimer's disease and other tauopathies. Here, we have evaluated whether GSK-3 is also able to modulate tau-mRNA splicing. Our data demonstrate that GSK-3 inhibition in cultured neurons affects tau splicing resulting in an increase in tau mRNA containing exon 10. Pre-mRNA splicing is catalyzed by a multimolecular complex including members of the serine/arginine-rich (SR) family of splicing factors. Immunofluorescence studies showed that after GSK-3 inhibition, SC35, a member of the SR family, is redistributed and enriched in nuclear speckles and colocalizes with the kinase. Furthermore, immunoprecipitated SC35 is phosphorylated by recombinant GSK-3␤. Phosphorylation of a peptide from the SR domain by GSK-3 revealed that the peptide needs to be prephosphorylated, suggesting the involvement of a priming kinase. Our results demonstrate that GSK-3 plays a crucial role in tau exon 10 splicing, raising the possibility that GSK3 could contribute to tauopathies via aberrant tau splicing.

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TAU as a Susceptibility Gene for Amyotropic Lateral Sclerosis–Parkinsonism Dementia Complex of Guam

Poorkaj¹

2001

Arch Neurol

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Determinants of 4-Repeat Tau Expression

Abstract: Results with double mutations demonstrate that the ESE and the intronic inhibitory element collaborate to regulate splicing. Thus splicing of tau E10 is regulated by a complex set of cis-acting elements that span nearly the entire exon and also include intronic sequences.

Cited by 122 publications

References 34 publications

Tau Exons 2 and 10, Which Are Misregulated in Neurodegenerative Diseases, Are Partly Regulated by Silencers Which Bind a SRp30c·SRp55 Complex That Either Recruits or Antagonizes htra2β1

Tau Exons 2 and 10, Which Are Misregulated in Neurodegenerative Diseases, Are Partly Regulated by Silencers Which Bind a SRp30c·SRp55 Complex That Either Recruits or Antagonizes htra2β1

Glycogen Synthase Kinase-3 Plays a Crucial Role in Tau Exon 10 Splicing and Intranuclear Distribution of SC35

TAU as a Susceptibility Gene for Amyotropic Lateral Sclerosis–Parkinsonism Dementia Complex of Guam

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