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, Akira Maeda

研究成果: Article

22 引用 (Scopus)

抄録

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

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Presenilin-2
High Mobility Group Proteins
RNA Precursors
Exons
Alzheimer Disease
RNA Splice Sites
Protein Binding
RNA
Endoplasmic Reticulum Stress
U1 Small Nuclear Ribonucleoproteins
Trans-Activators
Amyloid
Neurodegenerative Diseases
Transfection
Protein Isoforms
Cell Death
Binding Sites
Peptides

All Science Journal Classification (ASJC) codes

  • Genetics
  • Cell Biology

これを引用

Manabe, Takayuki ; Ohe, Kenji ; Katayama, Taiichi ; Matsuzaki, Shinsuke ; Yanagita, Takeshi ; Okuda, Hiroaki ; Bando, Yoshio ; Imaizumi, Kazunori ; Reeves, Raymond ; Tohyama, Masaya ; Maeda, Akira. / HMGA1a : Sequence-specific RNA-binding factor causing sporadic Alzheimer's disease-linked exon skipping of presenilin-2 pre-mRNA. :: Genes to Cells. 2007 ; 巻 12, 番号 10. pp. 1179-1191.
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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-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.",
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Manabe, T, Ohe, K, Katayama, T, Matsuzaki, S, Yanagita, T, Okuda, H, Bando, Y, Imaizumi, K, Reeves, R, Tohyama, M & Maeda, A 2007, 'HMGA1a: Sequence-specific RNA-binding factor causing sporadic Alzheimer's disease-linked exon skipping of presenilin-2 pre-mRNA', Genes to Cells, 巻. 12, 番号 10, pp. 1179-1191. https://doi.org/10.1111/j.1365-2443.2007.01123.x

HMGA1a : Sequence-specific RNA-binding factor causing sporadic Alzheimer's disease-linked exon skipping of presenilin-2 pre-mRNA. / Manabe, Takayuki; Ohe, Kenji; Katayama, Taiichi; Matsuzaki, Shinsuke; Yanagita, Takeshi; Okuda, Hiroaki; Bando, Yoshio; Imaizumi, Kazunori; Reeves, Raymond; Tohyama, Masaya; Maeda, Akira.

:: Genes to Cells, 巻 12, 番号 10, 01.10.2007, p. 1179-1191.

研究成果: Article

TY - JOUR

T1 - HMGA1a

T2 - Sequence-specific RNA-binding factor causing sporadic Alzheimer's disease-linked exon skipping of presenilin-2 pre-mRNA

AU - Manabe, Takayuki

AU - Ohe, Kenji

AU - Katayama, Taiichi

AU - Matsuzaki, Shinsuke

AU - Yanagita, Takeshi

AU - Okuda, Hiroaki

AU - Bando, Yoshio

AU - Imaizumi, Kazunori

AU - Reeves, Raymond

AU - Tohyama, Masaya

AU - Maeda, Akira

PY - 2007/10/1

Y1 - 2007/10/1

N2 - 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.

AB - 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.

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