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, Akira Maeda, M. Tohyama

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)698-708
Number of pages11
JournalCell Death and Differentiation
Volume10
Issue number6
DOIs
Publication statusPublished - 01-06-2003

Fingerprint

HMGA Proteins
Presenilin-2
RNA Precursors
Exons
U1 Small Nuclear Ribonucleoproteins
Alzheimer Disease
RNA Splice Sites
High Mobility Group Proteins
Trans-Activators
Neuroblastoma
Protein Isoforms
Proteins
Mutation
Brain
Genes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Manabe, T. ; Katayama, T. ; Sato, N. ; Gomi, F. ; Hitomi, J. ; Yanagita, T. ; Kudo, T. ; Honda, A. ; Mori, Y. ; Matsuzaki, S. ; Imaizumi, K. ; Maeda, Akira ; Tohyama, M. / Induced HMGA 1a expression causes aberrant splicing a Presenilin-2 pre-mRNA in sporadic Alzhiemer's disease. In: Cell Death and Differentiation. 2003 ; Vol. 10, No. 6. pp. 698-708.
@article{d41002f3af774db7b5283dc16b36705b,
title = "Induced HMGA 1a expression causes aberrant splicing a Presenilin-2 pre-mRNA in sporadic Alzhiemer's disease",
abstract = "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.",
author = "T. Manabe and T. Katayama and N. Sato and F. Gomi and J. Hitomi and T. Yanagita and T. Kudo and A. Honda and Y. Mori and S. Matsuzaki and K. Imaizumi and Akira Maeda and M. Tohyama",
year = "2003",
month = "6",
day = "1",
doi = "10.1038/sj.cdd.4401221",
language = "English",
volume = "10",
pages = "698--708",
journal = "Cell Death and Differentiation",
issn = "1350-9047",
publisher = "Nature Publishing Group",
number = "6",

}

Manabe, T, Katayama, T, Sato, N, Gomi, F, Hitomi, J, Yanagita, T, Kudo, T, Honda, A, Mori, Y, Matsuzaki, S, Imaizumi, K, Maeda, 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, vol. 10, no. 6, pp. 698-708. https://doi.org/10.1038/sj.cdd.4401221

Induced HMGA 1a expression causes aberrant splicing a Presenilin-2 pre-mRNA in sporadic Alzhiemer's disease. / Manabe, T.; Katayama, T.; Sato, N.; Gomi, F.; Hitomi, J.; Yanagita, T.; Kudo, T.; Honda, A.; Mori, Y.; Matsuzaki, S.; Imaizumi, K.; Maeda, Akira; Tohyama, M.

In: Cell Death and Differentiation, Vol. 10, No. 6, 01.06.2003, p. 698-708.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Induced HMGA 1a expression causes aberrant splicing a Presenilin-2 pre-mRNA in sporadic Alzhiemer's disease

AU - Manabe, T.

AU - Katayama, T.

AU - Sato, N.

AU - Gomi, F.

AU - Hitomi, J.

AU - Yanagita, T.

AU - Kudo, T.

AU - Honda, A.

AU - Mori, Y.

AU - Matsuzaki, S.

AU - Imaizumi, K.

AU - Maeda, Akira

AU - Tohyama, M.

PY - 2003/6/1

Y1 - 2003/6/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0037636434&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037636434&partnerID=8YFLogxK

U2 - 10.1038/sj.cdd.4401221

DO - 10.1038/sj.cdd.4401221

M3 - Article

VL - 10

SP - 698

EP - 708

JO - Cell Death and Differentiation

JF - Cell Death and Differentiation

SN - 1350-9047

IS - 6

ER -