Decoy mRNAs reduce beta-amyloid precursor protein mRNA in neuronal cells.
Overproduction of amyloid precursor protein (APP) and beta-amyloid likely contribute to neurodegeneration in Alzheimer's disease (AD). In an effort to understand neuronal APP gene regulation, we identified a 52 base element (52sce) immediately downstream from the stop codon that stabilizes APP mRNA. Deletion of this domain drastically destabilized APP mRNAs and reduced APP synthesis in vitro. Chimeric globin-APP mRNAs containing the globin coding sequence fused to the entire APP 3'-UTR, showed regulation similar to full-length APP mRNA. A variety of cytoplasmic lysates contain 52sce RNA binding activity, suggesting cis-trans interactions regulate the element's functionality. Finally, the overexpression of chimeric mRNAs, containing the GFP coding sequence and APP 3'-UTR, dramatically reduced endogenous APP steady-state levels in SH-SY5Y neuroblastoma cells and suggests a novel approach to reduce the amyloid burden in AD patients.
Westmark
Pamela R
PR
Department of Pathology and Laboratory Medicine, Neuroscience Training Program, Waisman Center for Developmental Disabilities and Institute on Aging, University of Wisconsin-Madison, 1500 Highland Avenue, Madison, WI 53705, USA.
Shin
Hyun C
HC
Westmark
Cara J
CJ
Soltaninassab
Syrus R
SR
Reinke
Emily K
EK
Malter
James S
JS