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Part 1: Document Description
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Citation |
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Title: |
Artificial enforcement of the unfolded protein response (UPR) reduces disease features in multiple preclinical models of ALS/FTD. |
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Identification Number: |
doi:10.34691/UCHILE/4MDLCP |
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Distributor: |
Repositorio de datos de investigación de la Universidad de Chile |
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Date of Distribution: |
2024-05-30 |
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Version: |
2 |
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Bibliographic Citation: |
Hetz, Claudio; Vicente Valenzuela; Daniela Becerra; José Astorga; Matias Fuentealba; Guillermo Diaz; Leslie Bargsted; Carlos Chacón; Alexis Martinez; Romina Gozalvo; Kasey Jackson; Vania Morales; Macarena Las Heras; Giovanni Tamburini; Leonard Petrucelli; Pablo Sardi; Lars Plate, 2024, "Artificial enforcement of the unfolded protein response (UPR) reduces disease features in multiple preclinical models of ALS/FTD.", https://doi.org/10.34691/UCHILE/4MDLCP, Repositorio de datos de investigación de la Universidad de Chile, V2 |
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Citation |
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Title: |
Artificial enforcement of the unfolded protein response (UPR) reduces disease features in multiple preclinical models of ALS/FTD. |
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Identification Number: |
doi:10.34691/UCHILE/4MDLCP |
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Authoring Entity: |
Hetz, Claudio (Universidad de Chile - Facultad de Medicina) |
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Vicente Valenzuela (Biomedical Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, Chile) |
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Daniela Becerra (Biomedical Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, Chile) |
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José Astorga (Biomedical Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, Chile) |
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Matias Fuentealba (Biomedical Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, Chile) |
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Guillermo Diaz (Biomedical Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, Chile) |
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Leslie Bargsted (Biomedical Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, Chile) |
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Carlos Chacón (Biomedical Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, Chile) |
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Alexis Martinez (Biomedical Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, Chile) |
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Romina Gozalvo (Biomedical Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, Chile) |
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Kasey Jackson (Sanofi Genzyme Corp., Cambridge Ma, USA) |
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Vania Morales (Sanofi Genzyme Corp., Cambridge Ma, USA) |
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Macarena Las Heras (Sanofi Genzyme Corp., Cambridge Ma, USA) |
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Giovanni Tamburini (Sanofi Genzyme Corp., Cambridge Ma, USA) |
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Leonard Petrucelli (Sanofi Genzyme Corp., Cambridge Ma, USA) |
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Pablo Sardi (Sanofi Genzyme Corp., Cambridge Ma, USA) |
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Lars Plate (Sanofi Genzyme Corp., Cambridge Ma, USA) |
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Distributor: |
Repositorio de datos de investigación de la Universidad de Chile |
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Access Authority: |
Hetz, Claudio |
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Depositor: |
Hetz, Claudio |
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Date of Deposit: |
2024-05-30 |
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Holdings Information: |
https://doi.org/10.34691/UCHILE/4MDLCP |
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Study Scope |
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Keywords: |
Medicine, Health and Life Sciences |
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Abstract: |
Data used for Research Article submission to Molecular Therapy Journal for review Amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) are part of a spectrum of diseases that share several causative genes, resulting on a combinatory of motor and cognitive symptoms and abnormal protein aggregation. Multiple unbiased studies have revealed that proteostasis impairment at the level of the endoplasmic reticulum (ER) is a transversal pathogenic feature of ALS/FTD. The transcription factor XBP1s is a master regulator of the unfolded protein response (UPR), the main adaptive pathway to cope with ER stress. Here we provide evidence of suboptimal activation of the UPR in ALS/FTD models under experimental ER stress. To artificially engage the UPR, we intracerebroventricularly administrated adeno-associated viruses (AAV) to express the active form of XBP1 (XBP1s) in the nervous system of ALS/FTD models. XBP1s expression improved motor performance and extended life span of mutant SOD1 mice, associated with reduced protein aggregation. AAV-XBP1s administration also attenuated disease progression in models of TDP-43 and C9orf72 pathogenesis. Proteomic profiling of spinal cord tissue revealed that XBP1s overexpression improved proteostasis and modulated the expression of a cluster of synaptic and cell morphology proteins. Our results suggest that strategies to improve ER proteostasis may serve as a pan-therapeutic strategy to treat ALS/FTD. |
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Methodology and Processing |
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Sources Statement |
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Data Access |
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Other Study Description Materials |
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Label: |
Valenzuela et al. 2024 Figures Mol Ther_FINAL-1.pdf |
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Notes: |
application/pdf |