PT  - JOURNAL ARTICLE
AU  - René L. Vidal
AU  - Denisse Sepulveda
AU  - Paulina Troncoso-Escudero
AU  - Paula Garcia-Huerta
AU  - Constanza Gonzalez
AU  - Lars Plate
AU  - Carolina Jerez
AU  - José Canovas
AU  - Claudia A. Rivera
AU  - Valentina Castillo
AU  - Marisol Cisternas
AU  - Sirley Leal
AU  - Alexis Martinez
AU  - Julia Grandjean
AU  - Hilal A. Lashuel
AU  - Alberto J.M. Martin
AU  - Veronica Latapiat
AU  - Soledad Matus
AU  - S. Pablo Sardi
AU  - R. Luke Wiseman
AU  - Claudio Hetz
TI  - Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the unfolded protein response (UPR) in models of neurodegeneration
AID  - 10.1101/2020.11.17.387480
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.11.17.387480
4099  - http://biorxiv.org/content/early/2020/11/18/2020.11.17.387480.short
4100  - http://biorxiv.org/content/early/2020/11/18/2020.11.17.387480.full
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.