HMGA1a: sequence-specific RNA-binding factor causing sporadic Alzheimer's disease-linked exon skipping of presenilin-2 pre-mRNA |
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Authors: | Manabe Takayuki Ohe Kenji Katayama Taiichi Matsuzaki Shinsuke Yanagita Takeshi Okuda Hiroaki Bando Yoshio Imaizumi Kazunori Reeves Raymond Tohyama Masaya Mayeda Akila |
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Institution: | Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan. |
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Abstract: | 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-beta 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. |
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