Excessive release of inorganic polyphosphate by ALS/FTD astrocytes causes non-cell-autonomous toxicity to motoneurons

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dc.contributor.authorArredondo, Cristian
dc.contributor.authorCefaliello, Carolina
dc.contributor.authorDyrda, Agnieszka
dc.contributor.authorJury, Nur
dc.contributor.authorMartinez, Pablo
dc.contributor.authorDiaz, Ivan
dc.contributor.authorAmaro, Armando
dc.contributor.authorTran, Helene
dc.contributor.authorMorales, Danna
dc.contributor.authorPertusa, Maria
dc.contributor.authorStoica, Lorelei
dc.contributor.authorFritz, Elsa
dc.contributor.authorCorvalan, Daniela
dc.contributor.authorAbarzua, Sebastian
dc.contributor.authorMendez-Ruette, Maxs
dc.contributor.authorFernandez, Paola
dc.contributor.authorRojas, Fabiola
dc.contributor.authorKumar, Meenakshi Sundaram
dc.contributor.authorAguilar, Rodrigo
dc.contributor.authorAlmeida, Sandra
dc.contributor.authorWeiss, Alexandra
dc.contributor.authorBustos, Fernando J.
dc.contributor.authorGonzalez-Nilo, Fernando
dc.contributor.authorOtero, Carolina
dc.contributor.authorTevy, Maria Florencia
dc.contributor.authorBosco, Daryl A.
dc.contributor.authorSaez, Juan C.
dc.contributor.authorKahne, Thilo
dc.contributor.authorGao, Fen-Biao
dc.contributor.authorBerry, James D.
dc.contributor.authorNicholson, Katharine
dc.contributor.authorSena-Esteves, Miguel
dc.contributor.authorMadrid, Rodolfo
dc.contributor.authorVarela, Diego
dc.contributor.authorMontecino, Martin
dc.contributor.authorBrown, Robert H.
dc.contributor.authorvan Zundert, Brigitte
dc.date.accessioned2025-01-20T21:06:32Z
dc.date.available2025-01-20T21:06:32Z
dc.date.issued2022
dc.description.abstractNon-cell-autonomous mechanisms contribute to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), in which astrocytes release unidentified factors that are toxic to motoneurons (MNs). We report here that mouse and patient iPSC-derived astrocytes with diverse ALS/FTD-linked mutations (SOD1, TARDBP, and C9ORF72) display elevated levels of intracellular inorganic polyphosphate (polyP), a ubiquitous, negatively charged biopolymer. PolyP levels are also increased in astrocyte-conditioned media (ACM) from ALS/FTD astrocytes. ACM-mediated MN death is prevented by degrading or neutralizing polyP in ALS/FTD astrocytes or ACM. Studies further reveal that postmortem familial and sporadic ALS spinal cord sections display enriched polyP staining signals and that ALS cerebrospinal fluid (CSF) exhibits increased polyP concentrations. Our in vitro results establish excessive astrocyte-derived polyP as a critical factor in non-cell-autonomous MN degeneration and a potential therapeutic target for ALS/ FTD. The CSF data indicate that polyP might serve as a new biomarker for ALS/FTD.
dc.fuente.origenWOS
dc.identifier.doi10.1016/j.neuron.2022.02.010
dc.identifier.eissn1097-4199
dc.identifier.issn0896-6273
dc.identifier.urihttps://doi.org/10.1016/j.neuron.2022.02.010
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/93354
dc.identifier.wosidWOS:000806724800010
dc.issue.numero10
dc.language.isoen
dc.pagina.final+
dc.pagina.inicio1656
dc.revistaNeuron
dc.rightsacceso restringido
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleExcessive release of inorganic polyphosphate by ALS/FTD astrocytes causes non-cell-autonomous toxicity to motoneurons
dc.typeartículo
dc.volumen110
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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