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

2022; Cell Press; Volume: 110; Issue: 10 Linguagem: Inglês

10.1016/j.neuron.2022.02.010

1097-4199

Cristián Arredondo, Carolina Cefaliello, Agnieszka Dyrda, Nur Jury, Pablo Martínez, Iván Darío Parrado Díaz, Armando Amaro, Hélène Tran, Danna Morales, Marı́a Pertusa, Lorelei Stoica, Elsa Fritz, Daniela Corvalán, Sebastián Abarzúa, Maxs Méndez-Ruette, Paola Fernández, Fabiola Rojas, Meenakshi Sundaram Kumar, Rodrigo Aguilar, Sandra Almeida, Alexandra Weiss, Fernando J. Bustos, Fernando D. González‐Nilo, Carolina Otero, María Florencia Tevy, Daryl A. Bosco, Juan C. Sáez, Thilo Kähne, Fen‐Biao Gao, James Berry, Katharine Nicholson, Miguel Sena‐Esteves, Rodolfo Madrid, Diego Varela, Martı́n Montecino, Robert H. Brown, Brigitte van Zundert,

biodegradable polymer synthesis and properties

Non-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.