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.
I: Molecular Neurodegeneration, Bind 18, Nr. 1, 5, 2023.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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