Artificial enforcement of the unfolded protein response (UPR) reduces disease features in multiple preclinical models of ALS/FTD.doi:10.34691/UCHILE/4MDLCPRepositorio de datos de investigación de la Universidad de Chile2024-05-302Hetz, 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, V2Artificial enforcement of the unfolded protein response (UPR) reduces disease features in multiple preclinical models of ALS/FTD.doi:10.34691/UCHILE/4MDLCPHetz, ClaudioVicente ValenzuelaDaniela BecerraJosé AstorgaMatias FuentealbaGuillermo DiazLeslie BargstedCarlos ChacónAlexis MartinezRomina GozalvoKasey JacksonVania MoralesMacarena Las HerasGiovanni TamburiniLeonard PetrucelliPablo SardiLars PlateRepositorio de datos de investigación de la Universidad de ChileHetz, ClaudioHetz, Claudio2024-05-30Medicine, Health and Life SciencesData 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.Valenzuela et al. 2024 Figures Mol Ther_FINAL-1.pdfapplication/pdf