{"id":1573,"identifier":"UCHILE/4MDLCP","persistentUrl":"https://doi.org/10.34691/UCHILE/4MDLCP","protocol":"doi","authority":"10.34691","publisher":"Repositorio de datos de investigación de la Universidad de Chile","publicationDate":"2024-05-30","storageIdentifier":"file://10.34691/UCHILE/4MDLCP","datasetVersion":{"id":426,"datasetId":1573,"datasetPersistentId":"doi:10.34691/UCHILE/4MDLCP","storageIdentifier":"file://10.34691/UCHILE/4MDLCP","versionNumber":2,"versionMinorNumber":0,"versionState":"RELEASED","lastUpdateTime":"2024-05-30T14:29:34Z","releaseTime":"2024-05-30T14:29:34Z","createTime":"2024-05-30T14:29:00Z","license":{"name":"CC-BY 4.0","uri":"http://creativecommons.org/licenses/by/4.0"},"fileAccessRequest":true,"metadataBlocks":{"citation":{"displayName":"Citation Metadata","name":"citation","fields":[{"typeName":"title","multiple":false,"typeClass":"primitive","value":"Artificial enforcement of the unfolded protein response (UPR) reduces disease features in multiple preclinical models of ALS/FTD."},{"typeName":"author","multiple":true,"typeClass":"compound","value":[{"authorName":{"typeName":"authorName","multiple":false,"typeClass":"primitive","value":"Hetz, Claudio"},"authorAffiliation":{"typeName":"authorAffiliation","multiple":false,"typeClass":"primitive","value":"Universidad de Chile - Facultad de Medicina"},"authorIdentifierScheme":{"typeName":"authorIdentifierScheme","multiple":false,"typeClass":"controlledVocabulary","value":"ORCID"},"authorIdentifier":{"typeName":"authorIdentifier","multiple":false,"typeClass":"primitive","value":"0000-0003-1120-7966"}},{"authorName":{"typeName":"authorName","multiple":false,"typeClass":"primitive","value":"Vicente Valenzuela"},"authorAffiliation":{"typeName":"authorAffiliation","multiple":false,"typeClass":"primitive","value":"Biomedical Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, Chile"}},{"authorName":{"typeName":"authorName","multiple":false,"typeClass":"primitive","value":"Daniela Becerra"}},{"authorName":{"typeName":"authorName","multiple":false,"typeClass":"primitive","value":"José Astorga"}},{"authorName":{"typeName":"authorName","multiple":false,"typeClass":"primitive","value":"Matias Fuentealba"}},{"authorName":{"typeName":"authorName","multiple":false,"typeClass":"primitive","value":"Guillermo Diaz"}},{"authorName":{"typeName":"authorName","multiple":false,"typeClass":"primitive","value":"Leslie Bargsted"}},{"authorName":{"typeName":"authorName","multiple":false,"typeClass":"primitive","value":"Carlos Chacón"}},{"authorName":{"typeName":"authorName","multiple":false,"typeClass":"primitive","value":"Alexis Martinez"}},{"authorName":{"typeName":"authorName","multiple":false,"typeClass":"primitive","value":"Romina Gozalvo"}},{"authorName":{"typeName":"authorName","multiple":false,"typeClass":"primitive","value":"Kasey Jackson"},"authorAffiliation":{"typeName":"authorAffiliation","multiple":false,"typeClass":"primitive","value":"Sanofi Genzyme Corp., Cambridge Ma, USA"}},{"authorName":{"typeName":"authorName","multiple":false,"typeClass":"primitive","value":"Vania Morales"}},{"authorName":{"typeName":"authorName","multiple":false,"typeClass":"primitive","value":"Macarena Las Heras"}},{"authorName":{"typeName":"authorName","multiple":false,"typeClass":"primitive","value":"Giovanni Tamburini"}},{"authorName":{"typeName":"authorName","multiple":false,"typeClass":"primitive","value":"Leonard Petrucelli"}},{"authorName":{"typeName":"authorName","multiple":false,"typeClass":"primitive","value":"Pablo Sardi"}},{"authorName":{"typeName":"authorName","multiple":false,"typeClass":"primitive","value":"Lars Plate"}}]},{"typeName":"datasetContact","multiple":true,"typeClass":"compound","value":[{"datasetContactName":{"typeName":"datasetContactName","multiple":false,"typeClass":"primitive","value":"Hetz, Claudio"},"datasetContactAffiliation":{"typeName":"datasetContactAffiliation","multiple":false,"typeClass":"primitive","value":"Universidad de Chile - Facultad de Medicina"},"datasetContactEmail":{"typeName":"datasetContactEmail","multiple":false,"typeClass":"primitive","value":"chetz@uchile.cl"}}]},{"typeName":"dsDescription","multiple":true,"typeClass":"compound","value":[{"dsDescriptionValue":{"typeName":"dsDescriptionValue","multiple":false,"typeClass":"primitive","value":"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."},"dsDescriptionDate":{"typeName":"dsDescriptionDate","multiple":false,"typeClass":"primitive","value":"2024-05-30"}}]},{"typeName":"subject","multiple":true,"typeClass":"controlledVocabulary","value":["Medicine, Health and Life Sciences"]},{"typeName":"depositor","multiple":false,"typeClass":"primitive","value":"Hetz, Claudio"},{"typeName":"dateOfDeposit","multiple":false,"typeClass":"primitive","value":"2024-05-30"}]}},"files":[{"label":"Valenzuela et al. 2024 Figures Mol Ther_FINAL-1.pdf","restricted":false,"version":1,"datasetVersionId":426,"dataFile":{"id":1574,"persistentId":"doi:10.34691/UCHILE/4MDLCP/K2H1P4","pidURL":"https://doi.org/10.34691/UCHILE/4MDLCP/K2H1P4","filename":"Valenzuela et al. 2024 Figures Mol Ther_FINAL-1.pdf","contentType":"application/pdf","filesize":212497,"storageIdentifier":"file://18fc9e769dc-57ed7db986cd","rootDataFileId":-1,"md5":"db52ede429bd95866288f502db35a4a1","checksum":{"type":"MD5","value":"db52ede429bd95866288f502db35a4a1"},"creationDate":"2024-05-30"}}],"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"}}