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Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the unfolded protein response (UPR) in models of neurodegeneration

View ORCID ProfileRené L. Vidal, Denisse Sepulveda, Paulina Troncoso-Escudero, Paula Garcia-Huerta, Constanza Gonzalez, Lars Plate, Carolina Jerez, José Canovas, Claudia A. Rivera, Valentina Castillo, Marisol Cisternas, Sirley Leal, Alexis Martinez, Julia Grandjean, Hilal A. Lashuel, Alberto J.M. Martin, Veronica Latapiat, Soledad Matus, S. Pablo Sardi, View ORCID ProfileR. Luke Wiseman, Claudio Hetz
doi: https://doi.org/10.1101/2020.11.17.387480
René L. Vidal
1Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
2Center for Integrative Biology, Universidad Mayor, Santiago, Chile
3Center for Geroscience, Brain Health and Metabolism, Santiago, Chile
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  • ORCID record for René L. Vidal
  • For correspondence: rene.vidal@umayor.cl chetz@med.uchile.cl chetz@buckinstitute.org
Denisse Sepulveda
1Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
2Center for Integrative Biology, Universidad Mayor, Santiago, Chile
3Center for Geroscience, Brain Health and Metabolism, Santiago, Chile
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Paulina Troncoso-Escudero
1Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
2Center for Integrative Biology, Universidad Mayor, Santiago, Chile
3Center for Geroscience, Brain Health and Metabolism, Santiago, Chile
4Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
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Paula Garcia-Huerta
1Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
3Center for Geroscience, Brain Health and Metabolism, Santiago, Chile
4Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
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Constanza Gonzalez
1Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
3Center for Geroscience, Brain Health and Metabolism, Santiago, Chile
4Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
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Lars Plate
5Department of Chemistry, Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA
6Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
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Carolina Jerez
1Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
3Center for Geroscience, Brain Health and Metabolism, Santiago, Chile
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José Canovas
4Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
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Claudia A. Rivera
1Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
2Center for Integrative Biology, Universidad Mayor, Santiago, Chile
3Center for Geroscience, Brain Health and Metabolism, Santiago, Chile
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Valentina Castillo
1Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
2Center for Integrative Biology, Universidad Mayor, Santiago, Chile
3Center for Geroscience, Brain Health and Metabolism, Santiago, Chile
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Marisol Cisternas
1Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
2Center for Integrative Biology, Universidad Mayor, Santiago, Chile
3Center for Geroscience, Brain Health and Metabolism, Santiago, Chile
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Sirley Leal
1Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
2Center for Integrative Biology, Universidad Mayor, Santiago, Chile
3Center for Geroscience, Brain Health and Metabolism, Santiago, Chile
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Alexis Martinez
1Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
3Center for Geroscience, Brain Health and Metabolism, Santiago, Chile
4Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
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Julia Grandjean
6Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
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Hilal A. Lashuel
7Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
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Alberto J.M. Martin
8Centro de Genómica y Bioinformática, Facultad de Ciencias, Universidad Mayor, Santiago, Chile
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Veronica Latapiat
8Centro de Genómica y Bioinformática, Facultad de Ciencias, Universidad Mayor, Santiago, Chile
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Soledad Matus
1Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
3Center for Geroscience, Brain Health and Metabolism, Santiago, Chile
9Fundacion Ciencia Vida, Santiago, 7780272, Chile
10Facultad de Medicina y Ciencia, Universidad San Sebastián, Providencia, 7510157, Santiago, Chile
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S. Pablo Sardi
11Rare and Neurological Diseases Therapeutic Area, Sanofi, 49 New York Avenue, Framingham, MA, USA
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R. Luke Wiseman
6Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
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  • ORCID record for R. Luke Wiseman
Claudio Hetz
1Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
3Center for Geroscience, Brain Health and Metabolism, Santiago, Chile
4Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
12Buck Institute for Research on Aging, Novato, CA, 94945, USA
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  • For correspondence: rene.vidal@umayor.cl chetz@med.uchile.cl chetz@buckinstitute.org
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Abstract

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 Statement

The authors have declared no competing interest.

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Posted November 18, 2020.
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Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the unfolded protein response (UPR) in models of neurodegeneration
René L. Vidal, Denisse Sepulveda, Paulina Troncoso-Escudero, Paula Garcia-Huerta, Constanza Gonzalez, Lars Plate, Carolina Jerez, José Canovas, Claudia A. Rivera, Valentina Castillo, Marisol Cisternas, Sirley Leal, Alexis Martinez, Julia Grandjean, Hilal A. Lashuel, Alberto J.M. Martin, Veronica Latapiat, Soledad Matus, S. Pablo Sardi, R. Luke Wiseman, Claudio Hetz
bioRxiv 2020.11.17.387480; doi: https://doi.org/10.1101/2020.11.17.387480
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Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the unfolded protein response (UPR) in models of neurodegeneration
René L. Vidal, Denisse Sepulveda, Paulina Troncoso-Escudero, Paula Garcia-Huerta, Constanza Gonzalez, Lars Plate, Carolina Jerez, José Canovas, Claudia A. Rivera, Valentina Castillo, Marisol Cisternas, Sirley Leal, Alexis Martinez, Julia Grandjean, Hilal A. Lashuel, Alberto J.M. Martin, Veronica Latapiat, Soledad Matus, S. Pablo Sardi, R. Luke Wiseman, Claudio Hetz
bioRxiv 2020.11.17.387480; doi: https://doi.org/10.1101/2020.11.17.387480

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