دورية أكاديمية
FUS-ALS hiPSC-derived astrocytes impair human motor units through both gain-of-toxicity and loss-of-support mechanisms
| العنوان: | FUS-ALS hiPSC-derived astrocytes impair human motor units through both gain-of-toxicity and loss-of-support mechanisms |
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| المؤلفون: | Katarina Stoklund Dittlau, Lisanne Terrie, Pieter Baatsen, Axelle Kerstens, Lim De Swert, Rekin’s Janky, Nikky Corthout, Pegah Masrori, Philip Van Damme, Poul Hyttel, Morten Meyer, Lieven Thorrez, Kristine Freude, Ludo Van Den Bosch |
| المصدر: | Molecular Neurodegeneration, Vol 18, Iss 1, Pp 1-26 (2023) |
| بيانات النشر: | BMC, 2023. |
| سنة النشر: | 2023 |
| المجموعة: | LCC:Neurology. Diseases of the nervous system LCC:Geriatrics |
| مصطلحات موضوعية: | Amyotrophic lateral sclerosis, Astrocyte, Reactivity, Cytokines, Motor unit, Microfluidic, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6 |
| الوصف: | 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. Graphical Abstract |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1750-1326 |
| Relation: | https://doaj.org/toc/1750-1326 |
| DOI: | 10.1186/s13024-022-00591-3 |
| URL الوصول: | https://doaj.org/article/159fec2704ed48f18e22c67df6281138 |
| رقم الأكسشن: | edsdoj.159fec2704ed48f18e22c67df6281138 |
| قاعدة البيانات: | Directory of Open Access Journals |
Find this article in full text from Springer Verlag. 
Full Text Finder | تدمد: | 17501326 |
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| DOI: | 10.1186/s13024-022-00591-3 |