[Recent progress in 'HMGA1a' which causes aberrant splicing of Presenilin-2 pre-mRNA in sporadic Alzheimer's disease].
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(sAD). We found PS2V is hypoxia-inducible in SK-N-SH cells and purified a responsible trans-acting factor based on its binding to an exon 5 fragment. The factor was identified as the High Mobility Group protein A1a: (HMGA1a). HMGA1a bound to a specific sequence on exon5, located upstream of the 5'-splice site. HMGA1a expression was induced by hypoxia. Over-expression of HMGA1a generated PS2V, through interference with U1snRNP binding to the 5'-splice site and caused exon5 skipping. HMGA1a levels were increased in brain from sAD patients. We propose a novel mechanism of sAD that involves HMGA1a-induced aberrant splicing of PS2 pre-mRNA in the absence of any mutations.
Katayama
Taiichi
T
Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University.
Manabe
Takayuki
T
Tohyama
Masaya
M
D000544:Alzheimer Disease / Q000235:genetics*; D005091:Exons / Q000235:genetics; D025741:HMGA1a Protein / Q000032:analysis / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D053766:Presenilin-2; D012326:RNA Splicing
D008565:Membrane Proteins; C508861:PSEN2 protein, human; D053766:Presenilin-2; D025741:HMGA1a Protein