Neuromuscular organoids model spinal neuromuscular pathologies in C9orf72 amyotrophic lateral sclerosis

• Published in: Cell reports (Cambridge) 2024-03, Vol.43 (3), p.113892-113892, Article 113892
• Main Authors: Gao, Chong, Shi, Qinghua, Pan, Xue, Chen, Jiajia, Zhang, Yuhong, Lang, Jiali, Wen, Shan, Liu, Xiaodong, Cheng, Tian-Lin, Lei, Kai
• Format: Article
• Language: English
• Subjects: ALS; Amyotrophic Lateral Sclerosis - pathology; autophagy; C9orf72; C9orf72 Protein - genetics; C9orf72 Protein - metabolism; CP: Neuroscience; dipeptide repeat proteins; Dipeptides - metabolism; Dipeptides - pharmacology; DNA Repeat Expansion; Frontotemporal Dementia - genetics; Frontotemporal Dementia - pathology; GSK2606414; Humans; muscle denervation; neural degeneration; NMO; Proteins - genetics
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.113892

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. [Display omitted] •C9-ALS NMOs displayed neuromuscular defects•C9-ALS NMOs displayed the C9orf72-associated pathological features•C9-ALS NMOs showed neurodegenerative features•GSK2606414 attenuated C9-ALS NMOs dysfunctions In brief, Gao et al. developed an amyotrophic lateral sclerosis (ALS) model using neuromuscular organoids (NMOs) derived from ALS patients’ iPSCs. The NMOs generated from ALS patients’ iPSCs exhibited spinal neural and peripheral muscular pathologies that are relevant to ALS.