FUS-ALS hiPSC-derived astrocytes impair human motor units through both gain-of-toxicity and loss-of-support mechanisms

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FUS-ALS hiPSC-derived astrocytes impair human motor units through both gain-of-toxicity and loss-of-support mechanisms. / Stoklund Dittlau, Katarina; Terrie, Lisanne; Baatsen, Pieter; Kerstens, Axelle; De Swert, Lim; Janky, Rekin's; Corthout, Nikky; Masrori, Pegah; Van Damme, Philip; Hyttel, Poul; Meyer, Morten; Thorrez, Lieven; Freude, Kristine; Van Den Bosch, Ludo.

In: Molecular Neurodegeneration, Vol. 18, No. 1, 5, 2023.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Stoklund Dittlau, K, Terrie, L, Baatsen, P, Kerstens, A, De Swert, L, Janky, R, Corthout, N, Masrori, P, Van Damme, P, Hyttel, P, Meyer, M, Thorrez, L, Freude, K & Van Den Bosch, L 2023, 'FUS-ALS hiPSC-derived astrocytes impair human motor units through both gain-of-toxicity and loss-of-support mechanisms', Molecular Neurodegeneration, vol. 18, no. 1, 5. https://doi.org/10.1186/s13024-022-00591-3

APA

Stoklund Dittlau, K., Terrie, L., Baatsen, P., Kerstens, A., De Swert, L., Janky, R., Corthout, N., Masrori, P., Van Damme, P., Hyttel, P., Meyer, M., Thorrez, L., Freude, K., & Van Den Bosch, L. (2023). FUS-ALS hiPSC-derived astrocytes impair human motor units through both gain-of-toxicity and loss-of-support mechanisms. Molecular Neurodegeneration, 18(1), [5]. https://doi.org/10.1186/s13024-022-00591-3

Vancouver

Stoklund Dittlau K, Terrie L, Baatsen P, Kerstens A, De Swert L, Janky R et al. FUS-ALS hiPSC-derived astrocytes impair human motor units through both gain-of-toxicity and loss-of-support mechanisms. Molecular Neurodegeneration. 2023;18(1). 5. https://doi.org/10.1186/s13024-022-00591-3

Author

Stoklund Dittlau, Katarina ; Terrie, Lisanne ; Baatsen, Pieter ; Kerstens, Axelle ; De Swert, Lim ; Janky, Rekin's ; Corthout, Nikky ; Masrori, Pegah ; Van Damme, Philip ; Hyttel, Poul ; Meyer, Morten ; Thorrez, Lieven ; Freude, Kristine ; Van Den Bosch, Ludo. / FUS-ALS hiPSC-derived astrocytes impair human motor units through both gain-of-toxicity and loss-of-support mechanisms. In: Molecular Neurodegeneration. 2023 ; Vol. 18, No. 1.

Bibtex

@article{3b1f8c029fe8476c9a4b3f626b5e42c5,
title = "FUS-ALS hiPSC-derived astrocytes impair human motor units through both gain-of-toxicity and loss-of-support mechanisms",
abstract = "BACKGROUND: Astrocytes play a crucial, yet not fully elucidated role in the selective motor neuron pathology in amyotrophic lateral sclerosis (ALS). Among other responsibilities, astrocytes provide important neuronal homeostatic support, however this function is highly compromised in ALS. The establishment of fully human coculture systems can be used to further study the underlying mechanisms of the dysfunctional intercellular interplay, and has the potential to provide a platform for revealing novel therapeutic entry points.METHODS: In this study, we characterised human induced pluripotent stem cell (hiPSC)-derived astrocytes from FUS-ALS patients, and incorporated these cells into a human motor unit microfluidics model to investigate the astrocytic effect on hiPSC-derived motor neuron network and functional neuromuscular junctions (NMJs) using immunocytochemistry and live-cell recordings. FUS-ALS cocultures were systematically compared to their CRISPR-Cas9 gene-edited isogenic control systems.RESULTS: We observed a dysregulation of astrocyte homeostasis, which resulted in a FUS-ALS-mediated increase in reactivity and secretion of inflammatory cytokines. Upon coculture with motor neurons and myotubes, we detected a cytotoxic effect on motor neuron-neurite outgrowth, NMJ formation and functionality, which was improved or fully rescued by isogenic control astrocytes. We demonstrate that ALS astrocytes have both a gain-of-toxicity and loss-of-support function involving the WNT/β-catenin pathway, ultimately contributing to the disruption of motor neuron homeostasis, intercellular networks and NMJs.CONCLUSIONS: Our findings shine light on a complex, yet highly important role of astrocytes in ALS, and provides further insight in to their pathological mechanisms.",
keywords = "Humans, Amyotrophic Lateral Sclerosis/metabolism, Astrocytes/metabolism, Induced Pluripotent Stem Cells/metabolism, Motor Neurons/metabolism, Neuromuscular Junction, RNA-Binding Protein FUS/physiology",
author = "{Stoklund Dittlau}, Katarina and Lisanne Terrie and Pieter Baatsen and Axelle Kerstens and {De Swert}, Lim and Rekin's Janky and Nikky Corthout and Pegah Masrori and {Van Damme}, Philip and Poul Hyttel and Morten Meyer and Lieven Thorrez and Kristine Freude and {Van Den Bosch}, Ludo",
note = "{\textcopyright} 2023. The Author(s).",
year = "2023",
doi = "10.1186/s13024-022-00591-3",
language = "English",
volume = "18",
journal = "Molecular Neurodegeneration",
issn = "1750-1326",
publisher = "BioMed Central Ltd.",
number = "1",

}

RIS

TY - JOUR

T1 - FUS-ALS hiPSC-derived astrocytes impair human motor units through both gain-of-toxicity and loss-of-support mechanisms

AU - Stoklund Dittlau, Katarina

AU - Terrie, Lisanne

AU - Baatsen, Pieter

AU - Kerstens, Axelle

AU - De Swert, Lim

AU - Janky, Rekin's

AU - Corthout, Nikky

AU - Masrori, Pegah

AU - Van Damme, Philip

AU - Hyttel, Poul

AU - Meyer, Morten

AU - Thorrez, Lieven

AU - Freude, Kristine

AU - Van Den Bosch, Ludo

N1 - © 2023. The Author(s).

PY - 2023

Y1 - 2023

N2 - BACKGROUND: Astrocytes play a crucial, yet not fully elucidated role in the selective motor neuron pathology in amyotrophic lateral sclerosis (ALS). Among other responsibilities, astrocytes provide important neuronal homeostatic support, however this function is highly compromised in ALS. The establishment of fully human coculture systems can be used to further study the underlying mechanisms of the dysfunctional intercellular interplay, and has the potential to provide a platform for revealing novel therapeutic entry points.METHODS: In this study, we characterised human induced pluripotent stem cell (hiPSC)-derived astrocytes from FUS-ALS patients, and incorporated these cells into a human motor unit microfluidics model to investigate the astrocytic effect on hiPSC-derived motor neuron network and functional neuromuscular junctions (NMJs) using immunocytochemistry and live-cell recordings. FUS-ALS cocultures were systematically compared to their CRISPR-Cas9 gene-edited isogenic control systems.RESULTS: We observed a dysregulation of astrocyte homeostasis, which resulted in a FUS-ALS-mediated increase in reactivity and secretion of inflammatory cytokines. Upon coculture with motor neurons and myotubes, we detected a cytotoxic effect on motor neuron-neurite outgrowth, NMJ formation and functionality, which was improved or fully rescued by isogenic control astrocytes. We demonstrate that ALS astrocytes have both a gain-of-toxicity and loss-of-support function involving the WNT/β-catenin pathway, ultimately contributing to the disruption of motor neuron homeostasis, intercellular networks and NMJs.CONCLUSIONS: Our findings shine light on a complex, yet highly important role of astrocytes in ALS, and provides further insight in to their pathological mechanisms.

AB - BACKGROUND: Astrocytes play a crucial, yet not fully elucidated role in the selective motor neuron pathology in amyotrophic lateral sclerosis (ALS). Among other responsibilities, astrocytes provide important neuronal homeostatic support, however this function is highly compromised in ALS. The establishment of fully human coculture systems can be used to further study the underlying mechanisms of the dysfunctional intercellular interplay, and has the potential to provide a platform for revealing novel therapeutic entry points.METHODS: In this study, we characterised human induced pluripotent stem cell (hiPSC)-derived astrocytes from FUS-ALS patients, and incorporated these cells into a human motor unit microfluidics model to investigate the astrocytic effect on hiPSC-derived motor neuron network and functional neuromuscular junctions (NMJs) using immunocytochemistry and live-cell recordings. FUS-ALS cocultures were systematically compared to their CRISPR-Cas9 gene-edited isogenic control systems.RESULTS: We observed a dysregulation of astrocyte homeostasis, which resulted in a FUS-ALS-mediated increase in reactivity and secretion of inflammatory cytokines. Upon coculture with motor neurons and myotubes, we detected a cytotoxic effect on motor neuron-neurite outgrowth, NMJ formation and functionality, which was improved or fully rescued by isogenic control astrocytes. We demonstrate that ALS astrocytes have both a gain-of-toxicity and loss-of-support function involving the WNT/β-catenin pathway, ultimately contributing to the disruption of motor neuron homeostasis, intercellular networks and NMJs.CONCLUSIONS: Our findings shine light on a complex, yet highly important role of astrocytes in ALS, and provides further insight in to their pathological mechanisms.

KW - Humans

KW - Amyotrophic Lateral Sclerosis/metabolism

KW - Astrocytes/metabolism

KW - Induced Pluripotent Stem Cells/metabolism

KW - Motor Neurons/metabolism

KW - Neuromuscular Junction

KW - RNA-Binding Protein FUS/physiology

U2 - 10.1186/s13024-022-00591-3

DO - 10.1186/s13024-022-00591-3

M3 - Journal article

C2 - 36653804

VL - 18

JO - Molecular Neurodegeneration

JF - Molecular Neurodegeneration

SN - 1750-1326

IS - 1

M1 - 5

ER -

ID: 333614466