Neuromuscular organoids model spinal neuromuscular pathologies in C9orf72 amyotrophic lateral sclerosis
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved..
Hexanucleotide repeat expansions in the C9orf72 gene are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Due to the lack of trunk neuromuscular organoids (NMOs) from ALS patients' induced pluripotent stem cells (iPSCs), an organoid system was missing to model the trunk spinal neuromuscular neurodegeneration. With the C9orf72 ALS patient-derived iPSCs and isogenic controls, we used an NMO system containing trunk spinal cord neural and peripheral muscular tissues to show that the ALS NMOs could model peripheral defects in ALS, including contraction weakness, neural denervation, and loss of Schwann cells. The neurons and astrocytes in ALS NMOs manifested the RNA foci and dipeptide repeat proteins. Acute treatment with the unfolded protein response inhibitor GSK2606414 increased the glutamatergic muscular contraction 2-fold and reduced the dipeptide repeat protein aggregation and autophagy. This study provides an organoid system for spinal neuromuscular pathologies in ALS and its application for drug testing.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:43 |
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| Enthalten in: |
Cell reports - 43(2024), 3 vom: 26. März, Seite 113892 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gao, Chong [VerfasserIn] |
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| Links: |
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| Themen: |
ALS |
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| Anmerkungen: |
Date Completed 01.04.2024 Date Revised 01.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.celrep.2024.113892 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369217144 |
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| 520 | |a Hexanucleotide repeat expansions in the C9orf72 gene are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Due to the lack of trunk neuromuscular organoids (NMOs) from ALS patients' induced pluripotent stem cells (iPSCs), an organoid system was missing to model the trunk spinal neuromuscular neurodegeneration. With the C9orf72 ALS patient-derived iPSCs and isogenic controls, we used an NMO system containing trunk spinal cord neural and peripheral muscular tissues to show that the ALS NMOs could model peripheral defects in ALS, including contraction weakness, neural denervation, and loss of Schwann cells. The neurons and astrocytes in ALS NMOs manifested the RNA foci and dipeptide repeat proteins. Acute treatment with the unfolded protein response inhibitor GSK2606414 increased the glutamatergic muscular contraction 2-fold and reduced the dipeptide repeat protein aggregation and autophagy. This study provides an organoid system for spinal neuromuscular pathologies in ALS and its application for drug testing | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a C9orf72 | |
| 650 | 4 | |a CP: Neuroscience | |
| 650 | 4 | |a GSK2606414 | |
| 650 | 4 | |a NMO | |
| 650 | 4 | |a autophagy | |
| 650 | 4 | |a dipeptide repeat proteins | |
| 650 | 4 | |a muscle denervation | |
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| 700 | 1 | |a Shi, Qinghua |e verfasserin |4 aut | |
| 700 | 1 | |a Pan, Xue |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Jiajia |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yuhong |e verfasserin |4 aut | |
| 700 | 1 | |a Lang, Jiali |e verfasserin |4 aut | |
| 700 | 1 | |a Wen, Shan |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Xiaodong |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Tian-Lin |e verfasserin |4 aut | |
| 700 | 1 | |a Lei, Kai |e verfasserin |4 aut | |
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