A role for SC35 and hnRNPA1 in the determination of amyloid precursor protein isoforms

被引：71

作者：

Donev, R.

Newall, A.

Thome, J.

Sheer, D.

机构：

[1] Cardiff Univ, Sch Med, Dept Med Biochem & Immunol, Cardiff CF14 4XN, Wales

[2] Lincolns Inn Fields Labs, Canc Res UK London Res Inst, Human Cytogenet Lab, London, England

[3] Univ Coll Swansea, Sch Med, Swansea, W Glam, Wales

[4] Barts & London Queen Marys Sch Med & Dent, London E1 2AT, England

[5] Inst Cell & Mol Sci, Ctr Neurosci, London, England

来源：

MOLECULAR PSYCHIATRY | 2007年 / 12卷 / 07期

基金：

英国医学研究理事会;

关键词：

Alzheimer's disease; alternative splicing; amyloid beta-protein precursor; SR proteins; hnRNPA1; Alu elements;

D O I：

10.1038/sj.mp.4001971

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The beta-amyloid peptide (A beta) that accumulates in senile plaques in Alzheimer's disease is formed by cleavage of the amyloid precursor protein (APP). The APP gene has several intronic Alu elements inserted in either the sense or antisense orientation. In this study, we demonstrate that binding of SC35 and hnRNPA1 to Alu elements on either side of exon 7 in the transcribed pre-mRNA is involved in alternative splicing of APP exons 7 and 8. Neuronal cells transfected with the full-length form of APP secrete higher levels of A beta than cells transfected with the APP695 isoform lacking exons 7 and 8. Finally, we show that treatment of neuronal cells with estradiol results in increased expression of APP695, SC35 and hnRNPA1, and lowers the level of secreted A beta. An understanding of the regulation of splicing of APP may lead to the identification of new targets for treating Alzheimer's disease.

引用

收藏

页码：681 / 690

页数：10

相关论文

共 47 条

[1] Differential recruitment of nuclear receptor coactivators may determine alternative RNA splice site choice in target genes [J].

Auboeuf, D ;

Dowhan, DH ;

Kang, YK ;

Larkin, K ;

Lee, JW ;

Berget, SM ;

O'Malley, BW .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (08) :2270-2274

[2] Control of 3′ splice site choice in vivo by ASF/SF2 and hnRNP A1 [J].

Bai, YD ;

Lee, D ;

Yu, TD ;

Chasin, LA .

NUCLEIC ACIDS RESEARCH, 1999, 27 (04) :1126-1134

[3] Modulation of exon skipping by high-affinity hnRNP A1-binding sites and by intron elements that repress splice site utilization [J].

Blanchette, M ;

Chabot, B .

EMBO JOURNAL, 1999, 18 (07) :1939-1952

[4] Heterogeneous nuclear ribonucleoprotein A1 is a novel internal ribosome entry site trans-acting factor that modulates alternative initiation of translation of the fibroblast growth factor 2 mRNA [J].

Bonnal, S ;

Pileur, F ;

Orsini, C ;

Parker, F ;

Pujol, F ;

Prats, AC ;

Vagner, S .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (06) :4144-4153

[5] RNA-BINDING SPECIFICITY OF HNRNP A1 - SIGNIFICANCE OF HNRNP A1 HIGH-AFFINITY BINDING-SITES IN PRE-MESSENGER-RNA SPLICING [J].

BURD, CG ;

DREYFUSS, G .

EMBO JOURNAL, 1994, 13 (05) :1197-1204

[6] The amyloid β-protein precursor of Alzheimer's disease is degraded extracellularly by a Kunitz protease inhibitor domain-sensitive trypsin-like serine protease in cultures of chick sympathetic neurons [J].

Caswell, MD ;

San Mok, S ;

Henry, A ;

Cappai, R ;

Klug, G ;

Beyreuther, K ;

Masters, CL ;

Small, DH .

EUROPEAN JOURNAL OF BIOCHEMISTRY, 1999, 266 (02) :509-516

[7] Heterogeneous nuclear ribonucleoprotein (hnRNP) binding to hormone response elements: A cause of vitamin D resistance [J].

Chen, H ;

Hewison, M ;

Hu, B ;

Adams, JS .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (10) :6109-6114

[8] The Alu insertion in the CLCN5 gene of a patient with Dent's disease leads to exon 11 skipping [J].

Claverie-Martín, F ;

Flores, C ;

Antón-Gamero, M ;

González-Acosta, H ;

García-Nieto, V .

JOURNAL OF HUMAN GENETICS, 2005, 50 (07) :370-374

[9] Recruitment of heterogeneous nuclear ribonucleoprotein A1 in vivo to the LMP/TAP region of the major histocompatibility complex [J].

Donev, R ;

Horton, R ;

Beck, S ;

Doneva, T ;

Vatcheva, R ;

Bowen, WR ;

Sheer, D .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (07) :5214-5226

[10] HnRNP-A1 binds directly to double-stranded DNA in vitro within a 36 bp sequence [J].

Donev, RM ;

Doneva, TA ;

Bowen, WR ;

Sheer, D .

MOLECULAR AND CELLULAR BIOCHEMISTRY, 2002, 233 (1-2) :181-185

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