HMGA1a: sequence-specific RNA-binding factor causing sporadic Alzheimer's disease-linked exon skipping of presenilin-2 pre-mRNA.
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.
Manabe
Takayuki
T
Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
Ohe
Kenji
K
Katayama
Taiichi
T
Matsuzaki
Shinsuke
S
Yanagita
Takeshi
T
Okuda
Hiroaki
H
Bando
Yoshio
Y
Imaizumi
Kazunori
K
Reeves
Raymond
R
Tohyama
Masaya
M
Mayeda
Akila
A
D017398:Alternative Splicing; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005091:Exons; D025741:HMGA1a Protein / Q000378:metabolism* / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D053766:Presenilin-2 / Q000096:biosynthesis* / Q000235:genetics*; D012322:RNA Precursors / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D053766:Presenilin-2; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D025741:HMGA1a Protein