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

Cristian Arredondo; Carolina Cefaliello; Agnieszka Dyrda; Nur Jury; Pablo Martinez; Iván Díaz; Armando Amaro; Helene Tran; Danna Morales; Maria 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 González-Nilo; Carolina Otero; Maria Florencia Tevy; Daryl A. Bosco; Juan C. Sáez; Thilo Kähne; Fen Biao Gao; James D. Berry; Katharine Nicholson; Miguel Sena-Esteves; Rodolfo Madrid; Diego Varela; Martin Montecino; Robert H. Brown; Brigitte van Zundert

doi:10.1016/j.neuron.2022.02.010

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

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

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Resumen

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.

Idioma original	Inglés
Páginas (desde-hasta)	1656-1670.e12
Publicación	Neuron
Volumen	110
N.º	10
DOI	https://doi.org/10.1016/j.neuron.2022.02.010
Estado	Publicada - 18 may. 2022

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Neurociencias General

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10.1016/j.neuron.2022.02.010

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Arredondo, C., Cefaliello, C., Dyrda, A., Jury, N., Martinez, P., Díaz, I., Amaro, A., Tran, H., Morales, D., Pertusa, M., Stoica, L., Fritz, E., Corvalán, D., Abarzúa, S., Méndez-Ruette, M., Fernández, P., Rojas, F., Kumar, M. S., Aguilar, R., ... van Zundert, B. (2022). Excessive release of inorganic polyphosphate by ALS/FTD astrocytes causes non-cell-autonomous toxicity to motoneurons. Neuron, 110(10), 1656-1670.e12. https://doi.org/10.1016/j.neuron.2022.02.010

@article{78e3eb0274ab4ff78012ea9e922b22f6,

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

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.",

keywords = "ALS, astrocytes, C9ORF72, CSF, FTD, iPSCs, motor neurons, polyP, SOD1, TARDBP",

author = "Cristian Arredondo and Carolina Cefaliello and Agnieszka Dyrda and Nur Jury and Pablo Martinez and Iv{\'a}n D{\'i}az and Armando Amaro and Helene Tran and Danna Morales and Maria Pertusa and Lorelei Stoica and Elsa Fritz and Daniela Corval{\'a}n and Sebasti{\'a}n Abarz{\'u}a and Maxs M{\'e}ndez-Ruette and Paola Fern{\'a}ndez and Fabiola Rojas and Kumar, {Meenakshi Sundaram} and Rodrigo Aguilar and Sandra Almeida and Alexandra Weiss and Bustos, {Fernando J.} and Fernando Gonz{\'a}lez-Nilo and Carolina Otero and Tevy, {Maria Florencia} and Bosco, {Daryl A.} and S{\'a}ez, {Juan C.} and Thilo K{\"a}hne and Gao, {Fen Biao} and Berry, {James D.} and Katharine Nicholson and Miguel Sena-Esteves and Rodolfo Madrid and Diego Varela and Martin Montecino and Brown, {Robert H.} and {van Zundert}, Brigitte",

note = "Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",

year = "2022",

month = may,

day = "18",

doi = "10.1016/j.neuron.2022.02.010",

language = "English",

volume = "110",

pages = "1656--1670.e12",

journal = "Neuron",

issn = "0896-6273",

publisher = "Cell Press",

number = "10",

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Arredondo, C, Cefaliello, C, Dyrda, A, Jury, N, Martinez, P, Díaz, I, Amaro, A, Tran, H, Morales, D, Pertusa, M, Stoica, L, Fritz, E, Corvalán, D, Abarzúa, S, Méndez-Ruette, M, Fernández, P, Rojas, F, Kumar, MS, Aguilar, R, Almeida, S, Weiss, A, Bustos, FJ , González-Nilo, F , Otero, C, Tevy, MF, Bosco, DA, Sáez, JC, Kähne, T, Gao, FB, Berry, JD, Nicholson, K, Sena-Esteves, M, Madrid, R, Varela, D, Montecino, M, Brown, RH & van Zundert, B 2022, 'Excessive release of inorganic polyphosphate by ALS/FTD astrocytes causes non-cell-autonomous toxicity to motoneurons', Neuron, vol. 110, n.º 10, pp. 1656-1670.e12. https://doi.org/10.1016/j.neuron.2022.02.010

TY - JOUR

T1 - Excessive release of inorganic polyphosphate by ALS/FTD astrocytes causes non-cell-autonomous toxicity to motoneurons

AU - Arredondo, Cristian

AU - Cefaliello, Carolina

AU - Dyrda, Agnieszka

AU - Jury, Nur

AU - Martinez, Pablo

AU - Díaz, Iván

AU - Amaro, Armando

AU - Tran, Helene

AU - Morales, Danna

AU - Pertusa, Maria

AU - Stoica, Lorelei

AU - Fritz, Elsa

AU - Corvalán, Daniela

AU - Abarzúa, Sebastián

AU - Méndez-Ruette, Maxs

AU - Fernández, Paola

AU - Rojas, Fabiola

AU - Kumar, Meenakshi Sundaram

AU - Aguilar, Rodrigo

AU - Almeida, Sandra

AU - Weiss, Alexandra

AU - Bustos, Fernando J.

AU - González-Nilo, Fernando

AU - Otero, Carolina

AU - Tevy, Maria Florencia

AU - Bosco, Daryl A.

AU - Sáez, Juan C.

AU - Kähne, Thilo

AU - Gao, Fen Biao

AU - Berry, James D.

AU - Nicholson, Katharine

AU - Sena-Esteves, Miguel

AU - Madrid, Rodolfo

AU - Varela, Diego

AU - Montecino, Martin

AU - Brown, Robert H.

AU - van Zundert, Brigitte

PY - 2022/5/18

Y1 - 2022/5/18

N2 - 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.

AB - 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.

KW - ALS

KW - astrocytes

KW - C9ORF72

KW - CSF

KW - FTD

KW - iPSCs

KW - motor neurons

KW - polyP

KW - SOD1

KW - TARDBP

UR - http://www.scopus.com/inward/record.url?scp=85129960298&partnerID=8YFLogxK

U2 - 10.1016/j.neuron.2022.02.010

DO - 10.1016/j.neuron.2022.02.010

M3 - Article

C2 - 35276083

AN - SCOPUS:85129960298

SN - 0896-6273

VL - 110

SP - 1656-1670.e12

JO - Neuron

JF - Neuron

IS - 10

ER -

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

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