期刊
NATURE NEUROSCIENCE
卷 22, 期 11, 页码 1793-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41593-019-0498-9
关键词
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资金
- ALS Association Investigator Initiated Awards [2235, 3209, 8075]
- Frick Foundation
- Association Francaise contre les Myopathies [18280]
- Virtual Helmholtz Institute 'RNA dysmetabolism in ALS and FTD' (WP2)
- DZNE (Ulm site)
- agence nationale de la recherche (ToFU, EpiFUS)
- Bundesministerium fur Bildung und Forschung [BMBF01EK1611C]
- Max Planck Society
- Donders Center for Neuroscience
- ARSla
- fondation 'recherche sur le cerveau'
- Axa Banque Patrimoniale (Bourse recherche maladies rares)
- Fondation pour la recherche medicale (Equipe FRM)
- Muscular Dystrophy Association [MDA479773]
- EU Joint Programme-Neurodegenerative Disease Research (JPND) [ZonMW 733051075, ZonMW 733501073]
- ERC [ERC-2017-COG 770244]
Neuromuscular junction (NMJ) disruption is an early pathogenic event in amyotrophic lateral sclerosis (ALS). Yet, direct links between NMJ pathways and ALS-associated genes such as FUS, whose heterozygous mutations cause aggressive forms of ALS, remain elusive. In a knock-in Fus-ALS mouse model, we identified postsynaptic NMJ defects in newborn homozygous mutants that were attributable to mutant FUS toxicity in skeletal muscle. Adult heterozygous knock-in mice displayed smaller neuromuscular endplates that denervated before motor neuron loss, which is consistent with 'dying-back' neuronopathy. FUS was enriched in subsynaptic myonuclei, and this innervation-dependent enrichment was distorted in FUS-ALS. Mechanistically, FUS collaborates with the ETS transcription factor ERM to stimulate transcription of acetylcholine receptor genes. Co-cultures of induced pluripotent stem cell-derived motor neurons and myotubes from patients with FUS-ALS revealed endplate maturation defects due to intrinsic FUS toxicity in both motor neurons and myotubes. Thus, FUS regulates acetylcholine receptor gene expression in subsynaptic myonuclei, and muscle-intrinsic toxicity of ALS mutant FUS may contribute to dying-back motor neuronopathy.
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