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HMGA1a: sequence‐specific RNA‐binding factor causing sporadic Alzheimer's disease‐linked exon skipping of presenilin‐2 pre‐mRNA
Author(s) -
Manabe Takayuki,
Ohe Kenji,
Katayama Taiichi,
Matsuzaki Shinsuke,
Yanagita Takeshi,
Okuda Hiroaki,
Bando Yoshio,
Imaizumi Kazunori,
Reeves Raymond,
Tohyama Masaya,
Mayeda Akila
Publication year - 2007
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2007.01123.x
Subject(s) - exon skipping , exon , biology , rna splicing , microbiology and biotechnology , alternative splicing , rna , messenger rna , splicing factor , precursor mrna , rna binding protein , biochemistry , gene
Aberrant exon 5 skipping of presenilin‐2 (PS2) pre‐mRNA produces a deleterious protein isoform PS2V, which is almost exclusively observed in the brains of sporadic Alzheimer's disease patients. PS2V over‐expression in vivo enhances susceptibility to various endoplasmic reticulum (ER) stresses and increases production of amyloid‐β peptides. We previously purified and identified high mobility group A protein 1a (HMGA1a) as a trans ‐acting factor responsible for aberrant exon 5 skipping. Using heterologous pre‐mRNAs, here we demonstrate that a specific HMGA1a‐binding sequence in exon 5 adjacent to the 5′ splice site is necessary for HMGA1a to inactivate the 5′ splice site. An aberrant HMGA1a–U1 snRNP complex was detected on the HMGA1a‐binding site adjacent to the 5′ splice site during the early splicing reaction. A competitor 2′‐ O ‐methyl RNA (2′‐ O ‐Me RNA) consisting of the HMGA1a‐binding sequence markedly repressed exon 5 skipping of PS2 pre‐mRNA in vitro and in vivo . Finally, HMGA1a‐induced cell death under ER stress was prevented by transfection of the competitor 2′‐ O ‐Me RNA. These results provide insights into the molecular basis for PS2V‐associated neurodegenerative diseases that are initiated by specific RNA binding of HMGA1a.