10.34691/UCHILE/4MDLCPHetz, ClaudioClaudioHetz0000-0003-1120-7966Universidad de Chile - Facultad de MedicinaVicente ValenzuelaVicenteValenzuelaBiomedical Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, ChileDaniela BecerraDanielaBecerraJosé AstorgaJoséAstorgaMatias FuentealbaMatiasFuentealbaGuillermo DiazGuillermoDiazLeslie BargstedLeslieBargstedCarlos ChacónCarlosChacónAlexis MartinezAlexisMartinezRomina GozalvoRominaGozalvoKasey JacksonKaseyJacksonSanofi Genzyme Corp., Cambridge Ma, USAVania MoralesVaniaMoralesMacarena Las HerasMacarenaLas HerasGiovanni TamburiniGiovanniTamburiniLeonard PetrucelliLeonardPetrucelliPablo SardiPabloSardiLars PlateLarsPlateRepositorio de datos de investigación de la Universidad de Chile2024Medicine, Health and Life SciencesHetz, ClaudioClaudioHetzUniversidad de Chile - Facultad de Medicina2024-05-302024-05-30212497application/pdf2.0CC-BY 4.0Data 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.