Excessive Release of Inorganic Polyphosphate by ALS/FTD Astrocytes Causes Non-cell-autonomous Toxicity to Motoneurons

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2022 Mar 11

PMID 35276083

Authors

Cristian Arredondo

Carolina Cefaliello

Agnieszka Dyrda

Nur Jury

Pablo Martinez

Ivan Diaz

Armando Amaro

Helene Tran

Danna Morales

Maria Pertusa

Lorelei Stoica

Elsa Fritz

Daniela Corvalan

Sebastian Abarzua

Maxs Mendez-Ruette

Paola Fernandez

Fabiola Rojas

Meenakshi Sundaram Kumar

Rodrigo Aguilar

Sandra Almeida

Alexandra Weiss

Fernando J Bustos

Fernando Gonzalez-Nilo

Carolina Otero

Maria Florencia Tevy

Daryl A Bosco

Juan C Saez

Thilo Kahne

Fen-Biao Gao

James D Berry

Katharine Nicholson

Miguel Sena-Esteves

Rodolfo Madrid

Diego Varela

Martin Montecino

Robert H Brown

Brigitte van Zundert

Affiliations

Soon will be listed here.

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.

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