期刊
JOURNAL OF NEUROCHEMISTRY
卷 121, 期 5, 页码 763-773出版社
WILEY-BLACKWELL
DOI: 10.1111/j.1471-4159.2012.07680.x
关键词
Alzheimer disease; cis-acting elements; mRNA splicing; protease; trans-factor proteins
资金
- Alzheimer's Association [ZEN-08-91633]
- NIH [2R15GM074660]
J. Neurochem. (2012) 121, 763773. Abstract beta-Site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the transmembrane aspartyl protease that catalyzes the first cleavage step in the proteolysis of the APP to the amyloid beta-protein (A beta), a process involved in the pathogenesis of Alzheimer disease. BACE1 pre-mRNA undergoes complex alternative splicing, the regulation of which is not well understood. We identified a G-rich sequence within exon 3 of BACE1 involved in controlling splice site selection. Mutation of the G-rich sequence decreased use of the normal 5' splice site of exon 3, which leads to full-length and proteolytically active BACE1, and increased use of an alternative splice site, which leads to a shorter, essentially inactive isoform. Nuclease protection assays, nuclear magnetic resonance, and circular dichroism spectroscopy revealed that this sequence folds into a G-quadruplex structure. Several proteins were identified as capable of binding to the G-rich sequence, and one of these, heterogeneous nuclear ribonucleoprotein H, was found to regulate BACE1 exon 3 alternative splicing and in a manner dependent on the G-rich sequence. Knockdown of heterogeneous nuclear ribonucleoprotein H led to a decrease in the full-length BACE1 mRNA isoform as well as a decrease in A beta production from APP, suggesting new possibilities for therapeutic approaches to Alzheimers disease.
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