Abstract
Alzheimer’s disease (AD) is the most common form of dementia with no effective treatment options. A complete elucidation of its underlying molecular mechanisms, including the transcription regulation of genes critically involved in AD, may shed light on new therapeutic development. RPS23RG1 is a newly identified AD-associated gene, whose expression is decreased in AD and restoration can attenuate AD-like phenotypes in animal models. However, the transcription regulation of RPS23RG1 remains unknown. In this study, we explored the promoter of RPS23RG1 and identified its transcription initiation site (TSS) at 1525 bp upstream of the ATG translation start codon. Progressive deletion analysis determined the presence of a negative regulatory region and a positive regulatory region within nucleotide positions +1127 to +1187 and +732 to +1127 relative to the TSS (+1), respectively. We conducted a reporter system to screen for compounds that increase RPS23RG1 expression through antagonizing its negative regulatory elements and identified phenazopyridine. Importantly, we demonstrated that phenazopyridine not only promoted RPS23RG1/Rps23rg1 expression, but also reduced AD-like pathologies and cognitive impairments in the APP/PS1 AD model mice. We also determined a critical negative regulatory domain of RPS23RG1 within nucleotide positions +1177 to +1187 and found that the transcription factor SMAD3 bound to this domain. Inhibition of SMAD3 promoted RPS23RG1 expression. Moreover, phenazopyridine reduced SMAD3 binding to the RPS23RG1 promoter without affecting SMAD3 phosphorylation and nuclear localization. Taken together, our results determine the transcription regulation mechanism of RPS23RG1 and show that phenazopyridine has potential for AD treatment through regulating RPS23RG1 transcription.
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Funding
This work was supported by grants from National Natural Science Foundation of China (82130039 and U21A20361 to YwZ; 82001442 to DZ, and 92049202 and 92149303 to HX), National Key Research and Development Program of China (2018YFC2000400 to YwZ), and The Major Program of Brain Science and Brain-Like Intelligence Technology (2021ZD0202400 to HX).
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CW and YwZ designed research. CW and YZ carried out most molecular and animal studies. DZ, YH, and JX performed some molecular experiments. XZ and HL provided technical support. HX helped on data interpretation. YwZ supervised the project. CW and YwZ wrote the manuscript. All authors reviewed and approved the final paper.
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Wang, C., Zhang, Y., Zhao, D. et al. Phenazopyridine promotes RPS23RG1/Rps23rg1 transcription and ameliorates Alzheimer-associated phenotypes in mice. Neuropsychopharmacol. 47, 2042–2050 (2022). https://doi.org/10.1038/s41386-022-01373-7
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DOI: https://doi.org/10.1038/s41386-022-01373-7
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