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

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

doi:10.1016/j.neuron.2022.02.010

Cited by 36 publications

(45 citation statements)

References 87 publications

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“…As such, excessive polyP secretion by ALS astrocytes could be linked to excessive influx of calcium causing excitotoxicity in motor neurons (Fritz et al, 2013;Arredondo et al, 2022). Elevated levels of polyP have been found in glial cells from fALS and sALS patient spinal cord sections and in cerebrospinal fluid, further confirming its relevance for ALS (Arredondo et al, 2022).…”

Section: Toxic Gain Of Function Mechanismsmentioning

confidence: 95%

“…Studies using astrocyte-conditioned medium also tested the hypothesis whether astrocytic release of soluble factors could mediate toxic gain of function reactions (Nagai et al, 2007;Di Giorgio et al, 2008;Rojas et al, 2014). Multiple factors were proposed including the release of cytokines such as TNF-α, interleukin 6 (IL-6) and interleukin 1β (IL-1β) as well as inorganic polyphosphate (polyP), miRNA-containing extracellular vesicles, prostaglandins, nitric oxide (NO), and ROS (Figure 3) (Nagai et al, 2007;Di Giorgio et al, 2008;Marchetto et al, 2008;Mishra et al, 2016;Kia et al, 2018;Chen et al, 2019;Varcianna et al, 2019;Lee et al, 2020;Arredondo et al, 2022;Baofengfeng et al, 2022;Gomes et al, 2022;Jensen et al, 2022;Stoklund Dittlau et al, 2023). Additionally, upregulation of inflammatory genes targeting proinflammatory cytokines, chemokines and components of the complement cascade have been reported in both fALS and sALS (Di Giorgio et al, 2008;Marchetto et al, 2008;Haidet-Phillips et al, 2011;Stoklund Dittlau , 2023) in addition to inflammatory NF-κβ pathway upregulation in sALS astrocytes (Haidet-Phillips et al, 2011;Gomes et al, 2019).…”

Section: Toxic Gain Of Function Mechanismsmentioning

confidence: 99%

“…Excitotoxicity might also be mediated through a toxic gain of function independent of glutamate levels. Recently, it was shown that astrocyte-secreted polyP mediates motor neuron toxicity in cultures (Arredondo et al, 2022). PolyP is proposed to act as a gliotransmitter by regulating neuronal excitability through ion channel modulation resulting in an increase in action potentials (Stotz et al, 2014).…”

Section: Toxic Gain Of Function Mechanismsmentioning

confidence: 99%

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Why should we care about astrocytes in a motor neuron disease?

Dittlau

Bosch

2023

Front. Mol. Med

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Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults, causing progressive degeneration of motor neurons, which results in muscle atrophy, respiratory failure and ultimately death of the patients. The pathogenesis of ALS is complex, and extensive efforts have focused on unravelling the underlying molecular mechanisms with a large emphasis on the dying motor neurons. However, a recent shift in focus towards the supporting glial population has revealed a large contribution and influence in ALS, which stresses the need to explore this area in more detail. Especially studies into astrocytes, the residential homeostatic supporter cells of neurons, have revealed a remarkable astrocytic dysfunction in ALS, and therefore could present a target for new and promising therapeutic entry points. In this review, we provide an overview of general astrocyte function and summarize the current literature on the role of astrocytes in ALS by categorizing the potentially underlying molecular mechanisms. We discuss the current efforts in astrocyte-targeted therapy, and highlight the potential and shortcomings of available models.

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Section: Toxic Gain Of Function Mechanismsmentioning

confidence: 95%

Section: Toxic Gain Of Function Mechanismsmentioning

confidence: 99%

Section: Toxic Gain Of Function Mechanismsmentioning

confidence: 99%

See 1 more Smart Citation

Why should we care about astrocytes in a motor neuron disease?

Dittlau

Bosch

2023

Front. Mol. Med

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“…polyP impacts multiple processes in mammalian systems, including cell proliferation, angiogenesis, metabolism, − inflammation, and innate immunity. − We have extensively reported on the procoagulant effects of polyP, which has emerged as a promising therapeutic target in the development of new antithrombotic agents. , Since polyP acts as an accelerant of coagulation in normal hemostasis, rather than being required for initiation of coagulation, neutralization of the effects of polyP could be a novel approach for thrombosis management without bleeding risk. This is a considerable advantage compared to current anticoagulant agents which all carry bleeding risk.…”

Section: Discussionmentioning

confidence: 99%

Influence of Steric Shield on Biocompatibility and Antithrombotic Activity of Dendritic Polyphosphate Inhibitor

Abbina

Vappala

et al. 2022

Mol. Pharmaceutics

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The polyanion, inorganic polyphosphate (polyP), is a procoagulant molecule which has become a promising therapeutic target in the development of antithrombotics. Neutralizing polyP's prothrombotic activity using polycationic inhibitors is one of the viable strategies to design new polyP inhibitors. However, in this approach, a fine balance between the electrostatic interaction of polyP and the inhibitor is needed. Any unprotected polycations are known to interact with negatively charged blood components, potentially resulting in platelet activation, cellular toxicity, and bleeding. Thus, designing potent polycationic polyP inhibitors with good biocompatibility is a major challenge. Building on our previous research on universal heparin reversal agent (UHRA), we report polyP inhibitors with a modified steric shield design. The molecular weight, number of cationic binding groups, and the length of the polyethylene glycol (PEG) chains were varied to arrive at the desired inhibitor. We studied two different PEG lengths (mPEG-750 versus mPEG-350) on the polyglycerol scaffold and investigated their influence on biocompatibility and polyP neutralization activity. The polyP inhibitor with mPEG-750 brush layer, mPEG 750 UHRA-10, showed superior biocompatibility compared to its mPEG-350 analogs by a number of measured parameters without losing its neutralization activity. An increase in cationic binding groups (25 groups in mPEG 750 UHRA-8 and 32 in mPEG 750 UHRA-10 [HC]) did not alter the neutralization activity, which suggested that the mPEG-750 shield layer provides significant protection of cationic binding groups and thus helps to minimize unwanted nonspecific interactions. Furthermore, these modified polyP inhibitors are highly biocompatible compared to conventional polycations that have been previously used as polyP inhibitors (e.g., PAMAM dendrimers and polyethylenimine). Through this study, we demonstrated the importance of the design of steric shield toward highly biocompatible polyP inhibitors. This approach can be exploited in the design of highly biocompatible macromolecular inhibitors.

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“…The appeal of human in vitro cell models stems from the potential to recapitulate and elucidate the pathophysiology of numerous diseases, including neurodegenerative disorders. Patient-derived cell lines can address cellular and molecular pathways that complement other experimental model systems, such as stress, autophagy, and trafficking [1][2][3]. The utility of patient-derived cell models depends upon their ability to reliably reflect normal or pathophysiological processes.…”

Section: Introductionmentioning

confidence: 99%

Postmortem Human Dura Mater Cells Exhibit Phenotypic, Transcriptomic and Genetic Abnormalities that Impact their Use for Disease Modeling

Argouarch

Schultz

Yang

et al. 2022

Stem Cell Rev and Rep

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Patient-derived cells hold great promise for precision medicine approaches in human health. Human dermal fibroblasts have been a major source of cells for reprogramming and differentiating into specific cell types for disease modeling. Postmortem human dura mater has been suggested as a primary source of fibroblasts for in vitro modeling of neurodegenerative diseases. Although fibroblast-like cells from human and mouse dura mater have been previously described, their utility for reprogramming and direct differentiation protocols has not been fully established. In this study, cells derived from postmortem dura mater are directly compared to those from dermal biopsies of living subjects. In two instances, we have isolated and compared dermal and dural cell lines from the same subject. Notably, striking differences were observed between cells of dermal and dural origin. Compared to dermal fibroblasts, postmortem dura mater-derived cells demonstrated different morphology, slower growth rates, and a higher rate of karyotype abnormality. Dura mater-derived cells also failed to express fibroblast protein markers. When dermal fibroblasts and dura mater-derived cells from the same subject were compared, they exhibited highly divergent gene expression profiles that suggest dura mater cells originated from a mixed mural lineage. Given their postmortem origin, somatic mutation signatures of dura mater-derived cells were assessed and suggest defective DNA damage repair. This study argues for rigorous karyotyping of postmortem derived cell lines and highlights limitations of postmortem human dura mater-derived cells for modeling normal biology or disease-associated pathobiology. Graphical abstract

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

Cited by 36 publications

References 87 publications

Why should we care about astrocytes in a motor neuron disease?

Why should we care about astrocytes in a motor neuron disease?

Influence of Steric Shield on Biocompatibility and Antithrombotic Activity of Dendritic Polyphosphate Inhibitor

Postmortem Human Dura Mater Cells Exhibit Phenotypic, Transcriptomic and Genetic Abnormalities that Impact their Use for Disease Modeling

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