S-024 | Regulation of UPRmt-associated proteins mediated by canonical Wnt signaling: A new protective mechanism against AD pathology

Cellular and Molecular Neurobiology
Author: Angie Kim Torres Juacida | Email: aktorres@uc.cl

Angie K. Torres^1°2°3°, Rodrigo G. Mira^3°, Claudia Jara^2°,  Alejandra Catenaccio^2°, Cheril Tapia-Rojas, Nibaldo C. Inestrosa^3°

^1° Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
^2° Neurobiology of Aging Lab, Centro Ciencia & Vida, Fundación Ciencia & Vida, Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile
^3° Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Escuela de Medicina, Universidad de Magallanes, Punta Arenas, Chile

Canonical Wnt signaling activation induces the transcription of Wnt target genes by nuclear translocation of β-catenin, where it binds to TCF/LEF and CBP/p300. The activation of Wnt signaling reduces AD pathology and improves mitochondrial function by a poorly understood mechanism. In stress conditions, such as AD, the Mitochondrial Unfolded Protein Response (UPRmt) is activated, which induces mitochondrial chaperones and proteases expression. Interestingly, UPRmt activation reduces AD pathology and needs CBP/p300 to induce the expression of its responsive proteins, suggesting that canonical Wnt signaling might regulate UPRmt–associated proteins. By modulating canonical Wnt signaling in vitro, we observed that its activation increases the protein and mRNA levels of UPRmt proteins such as the UPRmt transcription factor ATF5, the mitochondrial chaperone Hsp60, and mitochondrial proteases such as Lonp1. The same regulation was observed in vivo, in mouse models and C. elegans, suggesting the conserved nature of this process. Also, the reduction in UPRmt signaling by the downregulation of ATF5 reduces the ability of Wnt/β-catenin signaling activation to decrease Aβ pathology and phosphorylated tau levels in the hippocampus of the 3xAD mouse model. Thus, our results propose a new mechanism by which canonical Wnt signaling reduces AD pathology, increasing the UPRmt-associated protein expression.
Funding: FONDECYT 1221178 and Ciencia & Vida FB210008 to CTR and IFAN-CORFO P19 of NCI.