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  3. Neuromuscular organoids model spinal neuromuscular pathologies in C9orf72 amyotrophic lateral sclerosis

Neuromuscular organoids model spinal neuromuscular pathologies in C9orf72 amyotrophic lateral sclerosis

  • Cell Rep. 2024 Mar 1;43(3):113892. doi: 10.1016/j.celrep.2024.113892.
Chong Gao 1,  Qinghua Shi 2,  Xue Pan 3,  Jiajia Chen 4,  Yuhong Zhang 4,  Jiali Lang 4,  Shan Wen 5,  Xiaodong Liu 5,  Tian-Lin Cheng 6,  Kai Lei 7
Affiliations

Affiliations

  • 1 Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China; Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China; Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, Institute of Brain and Cognitive Science, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, China.
  • 2 Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China; Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China; Fudan University, Shanghai, China.
  • 3 Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China; Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China; College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
  • 4 Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China; Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China.
  • 5 Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China; Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China; Research Center for Industries of the Future, Westlake University, Hangzhou, Zhejiang, China.
  • 6 Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institute of Pediatrics, National Children's Medical Center, Children's Hospital, Fudan University, Shanghai, China.
  • 7 Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China; Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China. Electronic address: leikai@westlake.edu.cn.
PMID: 38431841 DOI: 10.1016/j.celrep.2024.113892
Abstract

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.

Keywords

ALS; C9orf72; CP: Neuroscience; GSK2606414; NMO; autophagy; dipeptide repeat proteins; muscle denervation; neural degeneration.

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