Induced HMGA 1a expression causes aberrant splicing a Presenilin-2 pre-mRNA in sporadic Alzhiemer's disease

T. Manabe, T. Katayama, N. Sato, F. Gomi, J. Hitomi, T. Yanagita, T. Kudo, A. Honda, Y. Mori, S. Matsuzaki, K. Imaizumi, A. Mayeda, M. Tohyama

研究成果: Article

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The aberrant splicing isoform (PS2V), generated by exon 5 skipping of the Presenilin-2 (PS2) gene transcript, is a diagnostic feature of sporadic Alzheimer's disease (AD). We found PS2V is hypoxia-inducible in human neuroblastoma SK-N-SH cells. We purified a responsible trans-acting factor based on its binding to an exon 5 fragment. The factor was identified as the high mobility group A1a protein (HMGA1a; formerly HMG-I). HMGA1a bound to a specific sequence on exon 5, located upstream of the 5′ splice site. HMGA1a expression was induced by hypoxia and the protein was accumulated in the nuclear speckles with the endogenous splicing factor SC35. Overexpression of HMGA1a generated PS2V, but PS2V was repressed by cotransfection with the U1 snRNP 70K protein that has a strong affinity to HMGA1a. HMGA1a could interfere with U1 snRNP binding to the 5′ splice site and caused exon 5 skipping. HMGA1a levels were significantly increased in the brain tissue from sporadic AD patients. We propose a novel mechanism of sporadic AD that involves HMGA1a-induced aberrant splicing of PS2 pre-mRNA in the absence of any mutations.

元の言語English
ページ(範囲)698-708
ページ数11
ジャーナルCell Death and Differentiation
10
発行部数6
DOI
出版物ステータスPublished - 01-06-2003
外部発表Yes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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    Manabe, T., Katayama, T., Sato, N., Gomi, F., Hitomi, J., Yanagita, T., Kudo, T., Honda, A., Mori, Y., Matsuzaki, S., Imaizumi, K., Mayeda, A., & Tohyama, M. (2003). Induced HMGA 1a expression causes aberrant splicing a Presenilin-2 pre-mRNA in sporadic Alzhiemer's disease. Cell Death and Differentiation, 10(6), 698-708. https://doi.org/10.1038/sj.cdd.4401221