HMGA1a trapping of U1 snRNP at an authentic 5' splice site induces aberrant exon skipping in sporadic Alzheimer's disease.

Abstract

Overexpression of high-mobility group A protein 1a (HMGA1a) causes aberrant exon 5 skipping of the Presenilin-2 (PS2) pre-mRNA, which is almost exclusively detected in patients with sporadic Alzheimer's disease. An electrophoretic mobility shift assay confirmed aberrant U1 small nuclear ribonucleoprotein particle (snRNP)-HMGA1a complex formation (via the U1-70K component), with RNA containing a specific HMGA1a-binding site and an adjacent 5' splice site. Psoralen cross-linking analysis demonstrated that the binding of HMGA1a adjacent to the 5' splice site induces unusually extended association of U1 snRNP to the 5' splice site. As a result, spliceosome assembly across either the intron or the exon is arrested at an early ATP-independent stage. We conclude that the HMGA1a-induced aberrant exon skipping is caused by impaired dissociation of U1 snRNP from the 5' splice site, leading to a defect in exon definition. The proposed molecular mechanism has profound implications for other known posttranscriptional modulation strategies in various organisms, all of which are triggered by aberrant U1 snRNP binding.

• Authors: Kenji Ohe, Akila Mayeda
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 30 Issue 9 Pg. 2220-8 (May 2010) ISSN: 1098-5549 [Electronic] United States
• PMID: 20194618 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RNA Splice Sites
• Ribonucleoprotein, U1 Small Nuclear
• HMGA1a Protein

Topics

• Alzheimer Disease (genetics)
• Base Sequence
• Binding Sites
• Exons (genetics)
• HMGA1a Protein (metabolism)
• HeLa Cells
• Humans
• Introns (genetics)
• Models, Biological
• Molecular Sequence Data
• Protein Binding
• RNA Splice Sites (genetics)
• Ribonucleoprotein, U1 Small Nuclear (metabolism)
• Spliceosomes (metabolism)