HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE ADVANCED SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Manabe, T. Articles by Mayeda, A. Search for Related Content PubMed Articles by Manabe, T. Articles by Mayeda, A.

¹ Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
² Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136-1019, USA
³ Department of Anatomy, Asahikawa Medical College, Asahikawa, Hokkaido 078-8510, Japan
⁴ Division of Molecular and Cellular Biology, Department of Anatomy, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan
⁵ Department of Biochemistry and Biophysics, School of Molecular Biosciences, Washington State University, Pullman, WA 99164-4660, USA

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-ß 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.

^aThese authors contributed equally to this work and should be considered jointly as first author.

^bPresent address: Center for Developmental Biology, RIKEN Kobe Institute, Kobe, Hyogo 650-0047, Japan.

^cPresent address: Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.

^dPresent address: Department of Anatomy and Neuroscience, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.

^* Correspondence: E-mail: mayeda{at}fujita-hu.ac.jp