ArticleNeuron2022
Excessive release of inorganic polyphosphate by ALS/FTD astrocytes causes non-cell-autonomous toxicity to motoneurons.
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In one paragraph
Article in Neuron, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers, 1 of them a synthesis that pooled it.
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55citing papers in PubMed, 1 pooled it
9.3field-weighted citation impact, top 1% of its field
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Who cites it
55 citing papers in PubMed, 1 synthesis or guideline pooled it, 79 citations in OpenAlex.
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- Probing metazoan polyphosphate biology usingeLife · 2026Article
- Exploring the ALS Multistep Model.Brain sciences · 2026Review
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- Platelet Polyphosphate Signals Through NFκB to Induce Myofibroblast Differentiation.Biomolecules · 2025Article
- Activity and Heterogeneity of Astrocytes in Neurological Diseases: Molecular Mechanisms and Therapeutic Targets.MedComm · 2025Review
- Novel Dual Mechanism GRT-X Agonist Acting on Kv7 Potassium Channel/Translocator Protein Receptor Prevents Motoneuron Degeneration Following Exposure to Mouse and Human Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Astrocyte-Conditioned Media.ACS chemical neuroscience · 2025Article
- Inorganic Polyphosphate: An Emerging Regulator of Neuronal Bioenergetics and Its Implications in Neuroprotection.Biomolecules · 2025Review
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- Targeting common disease pathomechanisms to treat amyotrophic lateral sclerosis.Nature reviews. Neurology · 2025Review
- Boldine as a neuroprotective agent against motor neuron degeneration in models of amyotrophic lateral sclerosis.Frontiers in cellular neuroscience · 2025Article
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- Unravelling neuronal and glial differences in ceramide composition, synthesis, and sensitivity to toxicity.Communications biology · 2024Article
- Inflammatory cytokines disrupt astrocyte exosomal HepaCAM-mediated protection against neuronal excitotoxicity in the SOD1G93A ALS model.Science advances · 2024Article
- Skeletal myotubes expressing ALS mutant SOD1 induce pathogenic changes, impair mitochondrial axonal transport, and trigger motoneuron death.Molecular medicine (Cambridge, Mass.) · 2024Article
Corrections and comments
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Authors and funding
37 authors at 8 institutions in 3 countries.
Cristian ArredondoInstitute of Biomedical Sciences (ICB), Faculty of Medicine & Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile; CARE Biomedical Research Center, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
Carolina CefalielloDepartment of Neurology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
Agnieszka DyrdaInstitute of Biomedical Sciences (ICB), Faculty of Medicine & Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile; CARE Biomedical Research Center, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
Nur JuryInstitute of Biomedical Sciences (ICB), Faculty of Medicine & Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile; CARE Biomedical Research Center, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
Pablo MartinezInstitute of Biomedical Sciences (ICB), Faculty of Medicine & Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile; CARE Biomedical Research Center, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
Iván DíazInstitute of Biomedical Sciences (ICB), Faculty of Medicine & Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile; CARE Biomedical Research Center, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
Armando AmaroInstitute of Biomedical Sciences (ICB), Faculty of Medicine & Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile; CARE Biomedical Research Center, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
Helene TranDepartment of Neurology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
Danna MoralesProgram of Physiology and Biophysics, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile; Millennium Nucleus of Ion Channels-Associated Diseases (MiNICAD), Santiago 9160000, Chile.
Maria PertusaMillennium Nucleus of Ion Channels-Associated Diseases (MiNICAD), Santiago 9160000, Chile; Millennium Nucleus for the Study of Pain (MiNuSPain), Santiago 9160000, Chile; Department of Biology, Faculty of Chemistry and Biology, Universidad de Santiago de Chile, Santiago 9160000, Chile.
Lorelei StoicaDepartment of Neurology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA; Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Elsa FritzInstitute of Biomedical Sciences (ICB), Faculty of Medicine & Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile; CARE Biomedical Research Center, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
Daniela CorvalánInstitute of Biomedical Sciences (ICB), Faculty of Medicine & Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile; CARE Biomedical Research Center, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
Sebastián AbarzúaInstitute of Biomedical Sciences (ICB), Faculty of Medicine & Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile; CARE Biomedical Research Center, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile; FONDAP Center for Genome Regulation, Santiago 8370146, Chile.
Maxs Méndez-RuetteInstitute of Biomedical Sciences (ICB), Faculty of Medicine & Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile; CARE Biomedical Research Center, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
Paola FernándezInstituto de Neurociencias, Centro Interdisciplinario de Neurociencias de Valparaíso, Universidad de Valparaíso, Valparaíso 2340000, Chile.
Fabiola RojasInstitute of Biomedical Sciences (ICB), Faculty of Medicine & Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile; CARE Biomedical Research Center, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
Meenakshi Sundaram KumarDepartment of Neurology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
Rodrigo AguilarInstitute of Biomedical Sciences (ICB), Faculty of Medicine & Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile.
Sandra AlmeidaDepartment of Neurology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
Alexandra WeissDepartment of Neurology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
Fernando J BustosInstitute of Biomedical Sciences (ICB), Faculty of Medicine & Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile.
Fernando González-NiloInstituto de Neurociencias, Centro Interdisciplinario de Neurociencias de Valparaíso, Universidad de Valparaíso, Valparaíso 2340000, Chile; Center for Bioinformatics and Integrative Biology (CBIB), Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile.
Carolina OteroSchool of Chemistry and Pharmacy, Faculty of Medicine, Universidad Andres Bello, Santiago 8320000, Chile.
Maria Florencia TevyCell Biology Laboratory, INTA, University of Chile and GEDIS Biotech, Santiago 7810000, Chile.
Daryl A BoscoDepartment of Neurology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
Juan C SáezInstituto de Neurociencias, Centro Interdisciplinario de Neurociencias de Valparaíso, Universidad de Valparaíso, Valparaíso 2340000, Chile.
Thilo KähneInstitute of Experimental Internal Medicine, Medical School, Otto von Guericke University Magdeburg, Magdeburg 39120, Germany.
Fen-Biao GaoDepartment of Neurology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
James D BerryMassachusetts General Hospital Neurological Clinical Research Institute and Harvard Medical School, Boston, MA 02114, USA.
Katharine NicholsonMassachusetts General Hospital Neurological Clinical Research Institute and Harvard Medical School, Boston, MA 02114, USA.
Miguel Sena-EstevesDepartment of Neurology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA; Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Rodolfo MadridMillennium Nucleus of Ion Channels-Associated Diseases (MiNICAD), Santiago 9160000, Chile; Millennium Nucleus for the Study of Pain (MiNuSPain), Santiago 9160000, Chile; Department of Biology, Faculty of Chemistry and Biology, Universidad de Santiago de Chile, Santiago 9160000, Chile.
Diego VarelaProgram of Physiology and Biophysics, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile; Millennium Nucleus of Ion Channels-Associated Diseases (MiNICAD), Santiago 9160000, Chile.
Martin MontecinoInstitute of Biomedical Sciences (ICB), Faculty of Medicine & Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile; FONDAP Center for Genome Regulation, Santiago 8370146, Chile.
Robert H BrownDepartment of Neurology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
Brigitte van ZundertInstitute of Biomedical Sciences (ICB), Faculty of Medicine & Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile; CARE Biomedical Research Center, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile; Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA. Electronic address: bvanzundert@unab.cl.
Universidad Andrés Bello · CLUniversity of Massachusetts Chan Medical School · USHarvard University · USMillennium Nucleus of Ion Channel Associated Diseases · CLUniversidad de Santiago de Chile · CLUniversity of Valparaíso · CLOtto-von-Guericke-Universität Magdeburg · DEUniversity of Chile · CL
Funding
Expanding the chemical diversity of therapeutic oligonucleotides to treat neurodegenerative disordersR01NS104022 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI ANASTASIA KHVOROVA · 2017 to 2026
$6.0MMultimodal analysis and therapeutic targeting of aberrant nucleocytoplasmic compartmentalization in FUS-related neurodegenerative diseaseR01NS108769 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI Daryl Angela Bosco, Ankur Jain · 2019 to 2026
$5.2MNext-generation antisense therapeutics for ALS and frontotemporal dementiaR01NS111990 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI Robert H Brown, Jonathan K Watts · 2019 to 2026
$5.2MInvestigating Common Molecular Pathogenic Pathways in Frontotemporal Dementia Patients iPSC-Derived NeuronsR01NS057553 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI Fen-Biao Gao · 2008 to 2026
$4.5MInvestigating Pathogenic Mechanisms of Frontotemporal Dementia Caused by Mutations in CHMP2B and TBK1R37NS057553 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI GAO, FEN-BIAO · 2018 to 2024
$4.3MUnderstanding Frontotemporal Dementia Using Drosophila and iPSC ModelsR01NS101986 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI Fen-Biao Gao · 2017 to 2026
$3.6MUnderstanding Frontotemporal Dementia Using Drosophila and iPSC ModelsRF1NS101986 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI GAO, FEN-BIAO · 2022 to 2022
$2.1MCharacterization of TASK-1 Modulation of Dipeptide Repeat Protein-Mediated Toxicity in iPSC-derived C9ORF72 Patient Neurons.R21NS119952 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI ALMEIDA, SANDRA · 2020 to 2020
$461kInvestigating Translational De-repression as a Mechanism to Increase Progranulin Levels in iPSC-derived Patient NeuronsR21NS112766 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI ALMEIDA, SANDRA · 2019 to 2019
$461kRole of p38alpha signaling in mutant SOD1-linked motor neuron diseaseR21NS120126 · NINDS · UNIVERSITY OF ILLINOIS AT CHICAGO · PI BOSCO, DARYL ANGELA, MORFINI, GERARDO ANDRES · 2020 to 2020
$458kNINDS NIH HHS R01 NS057553NINDS NIH HHS R01 NS101986NINDS NIH HHS R01 NS104022NINDS NIH HHS R01 NS108769NINDS NIH HHS R01 NS111990NINDS NIH HHS R21 NS112766NINDS NIH HHS R21 NS119952NINDS NIH HHS R21 NS120126NINDS NIH HHS R37 NS057553NINDS NIH HHS RF1 NS101986
Abstract
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.
Indexed as
Amyotrophic Lateral SclerosisFrontotemporal DementiaAnimalsAstrocytesC9orf72 ProteinCulture Media, ConditionedHumansMiceMotor NeuronsPolyphosphatesC9orf72 ProteinCulture Media, ConditionedPolyphosphatesALSastrocytesC9ORF72CSFFTDiPSCsmotor neuronspolyPSOD1TARDBP
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