Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the UPR in models of neurodegeneration
Autor: | Paulina Troncoso-Escudero, R. Luke Wiseman, Veronica Latapiat, Constanza Gonzalez, Paula Garcia-Huerta, José Cánovas, Julia M. D. Grandjean, Rene L. Vidal, Lars Plate, S. Pablo Sardi, Alexis Martinez, Marisol Cisternas, Hilal A. Lashuel, Valentina Castillo, Claudia A Rivera, Soledad Matus, Denisse Sepulveda, Carolina Jerez, Sirley Leal, Alberto J. M. Martin, Donzelli Sonia, Claudio Hetz |
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Rok vydání: | 2021 |
Předmět: |
Male
X-Box Binding Protein 1 endoplasmic-reticulum stress Huntingtin XBP1 alpha-synuclein mouse model transcription factor xbp1s Biology quality-control proteins Mice 03 medical and health sciences 0302 clinical medicine Drug Discovery Genetics medicine Animals Humans Glucose homeostasis Molecular Biology 030304 developmental biology Pharmacology Huntingtin Protein 0303 health sciences ATF6 links er stress independent activation Neurodegeneration ATF4 Neurodegenerative Diseases unfolded protein response medicine.disease Activating Transcription Factor 6 Cell biology Disease Models Animal HEK293 Cells messenger-rnas Proteostasis Multiprotein Complexes glucose-homeostasis 030220 oncology & carcinogenesis Mutation Unfolded protein response Molecular Medicine Original Article |
Zdroj: | Mol Ther |
ISSN: | 1525-0016 |
Popis: | Alteration to endoplasmic reticulum (ER) proteostasis is observed in 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. In this study, 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 a stronger effect in reducing the abnormal aggregation of mutant huntingtin and α-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 disease and Huntington’s disease. These results support the concept in which 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. |
Databáze: | OpenAIRE |
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