FUS-mediated regulation of acetylcholine receptor transcription at neuromuscular junctions is compromised in amyotrophic lateral sclerosis.

Adult Amyotrophic Lateral Sclerosis / pathology Animals Cells, Cultured Female Gene Expression Regulation / physiology Gene Knock-In Techniques Humans Male Mice Mice, Knockout Motor Neurons / pathology Muscle Fibers, Skeletal / pathology Nerve Degeneration / physiopathology Neuromuscular Junction / metabolism RNA-Binding Protein FUS / genetics Receptors, Cholinergic / metabolism Young Adult

Journal

Nature neuroscience

ISSN: 1546-1726

Titre abrégé: Nat Neurosci

Pays: United States

ID NLM: 9809671

Informations de publication

Date de publication:
11 2019

Historique:

received: 17 05 2019

accepted: 15 08 2019

pubmed: 9 10 2019

medline: 1 2 2020

entrez: 9 10 2019

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41593-019-0498-9 PMID: 31591561 PMC: PMC6858880

pubmed: 31591561

doi: 10.1038/s41593-019-0498-9

pii: 10.1038/s41593-019-0498-9

pmc: PMC6858880

mid: EMS84086

doi:

Substances chimiques

FUS protein, mouse 0

RNA-Binding Protein FUS 0

Receptors, Cholinergic 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

1793-1805

Subventions

Organisme : European Research Council

ID : 770244

Pays : International

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