HMGA1a: Sequence-specific RNA-binding factor causing sporadic Alzheimer's disease-linked exon skipping of presenilin-2 pre-mRNA

Takayuki Manabe, Kenji Ohe, Taiichi Katayama, Shinsuke Matsuzaki, Takeshi Yanagita, Hiroaki Okuda, Yoshio Bando, Kazunori Imaizumi, Raymond Reeves, Masaya Tohyama, Akila Mayeda

研究成果: Article

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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.

元の言語English
ページ(範囲)1179-1191
ページ数13
ジャーナルGenes to Cells
12
発行部数10
DOI
出版物ステータスPublished - 01-10-2007

All Science Journal Classification (ASJC) codes

  • Genetics
  • Cell Biology

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    Manabe, T., Ohe, K., Katayama, T., Matsuzaki, S., Yanagita, T., Okuda, H., Bando, Y., Imaizumi, K., Reeves, R., Tohyama, M., & Mayeda, A. (2007). HMGA1a: Sequence-specific RNA-binding factor causing sporadic Alzheimer's disease-linked exon skipping of presenilin-2 pre-mRNA. Genes to Cells, 12(10), 1179-1191. https://doi.org/10.1111/j.1365-2443.2007.01123.x