RT Journal Article
SR Electronic
T1 Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the unfolded protein response (UPR) in models of neurodegeneration
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.11.17.387480
DO 10.1101/2020.11.17.387480
A1 René L. Vidal
A1 Denisse Sepulveda
A1 Paulina Troncoso-Escudero
A1 Paula Garcia-Huerta
A1 Constanza Gonzalez
A1 Lars Plate
A1 Carolina Jerez
A1 José Canovas
A1 Claudia A. Rivera
A1 Valentina Castillo
A1 Marisol Cisternas
A1 Sirley Leal
A1 Alexis Martinez
A1 Julia Grandjean
A1 Hilal A. Lashuel
A1 Alberto J.M. Martin
A1 Veronica Latapiat
A1 Soledad Matus
A1 S. Pablo Sardi
A1 R. Luke Wiseman
A1 Claudio Hetz
YR 2020
UL http://biorxiv.org/content/early/2020/11/18/2020.11.17.387480.abstract
AB Alteration to endoplasmic reticulum (ER) proteostasis is observed on a variety of neurodegenerative diseases associated with abnormal protein aggregation. Activation of the unfolded protein response (UPR) enables an adaptive reaction to recover ER proteostasis and cell function. The UPR is initiated by specialized stress sensors that engage gene expression programs through the concerted action of the transcription factors ATF4, ATF6f, and XBP1s. Although UPR signaling is generally studied as unique linear signaling branches, correlative evidence suggests that ATF6f and XBP1s may physically interact to regulate a subset of UPR-target genes. Here, we designed an ATF6f-XBP1s fusion protein termed UPRplus that behaves as a heterodimer in terms of its selective transcriptional activity. Cell-based studies demonstrated that UPRplus has stronger an effect in reducing the abnormal aggregation of mutant huntingtin and alpha-synuclein when compared to XBP1s or ATF6 alone. We developed a gene transfer approach to deliver UPRplus into the brain using adeno-associated viruses (AAVs) and demonstrated potent neuroprotection in vivo in preclinical models of Parkinson’s and Huntington’s disease. These results support the concept where directing UPR-mediated gene expression toward specific adaptive programs may serve as a possible strategy to optimize the beneficial effects of the pathway in different disease conditions.Competing Interest StatementThe authors have declared no competing interest.