Abstract
An unusual stop codon readthrough event generates a conserved C-terminally elongated variant of the water channel protein Aquaporin 4 (AQP4). In the brain, AQP4 is astrocyte-specific, required for normal functioning of the glymphatic system, and involved in the clearance of the Alzheimer’s associated protein Amyloid beta. Further, the readthrough variant is localized exclusively perivascularly, and the perivascular pool of AQP4 is reduced in Alzheimer’s and several other neurological diseases. However, there are currently no means of increasing or restoring the perivascular pool AQP4. Here we identify a compound that can enhance Aqp4 stop codon readthrough. We screened 2600 compounds, mostly approved drugs and pharmacologically active natural compounds, using a luciferase reporter system. 28 candidate lead compounds were then subjected to a variety of secondary screening steps using orthogonal reporter systems and characterizing dose-response activities. Finally, we tested the top compounds’ abilities to generate readthrough of the endogenous Aqp4 transcript, identifying Apigenin as an enhancer of this biological phenomenon. This compound can allow modulation of readthrough in experimental systems, mechanistic studies of programmed readthrough, and suggests the potential for modulating Alzheimer’s disease through pharmacological enhancement of perivascular AQP4.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Contact Information: Dr. Joseph Dougherty, Department of Genetics, Campus Box 8232, 4566 Scott Ave., St. Louis, MO. 63110-1093, P: 314-286-0752, F: 314-362-7855, E:jdougherty{at}genetics.wustl.edu