Journal Article

DZNE-2020-07902

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png FUS-mediated regulation of acetylcholine receptor transcription at neuromuscular junctions is compromised in amyotrophic lateral sclerosis.

Picchiarelli, G. ; Demestre, M. ; Zuko, A. ; Been, M. ; Higelin, J. ; Dieterlé, S. ; Goy, M.-A. ; Mallik, M. ; Sellier, C. ; Scekic-Zahirovic, J. ; Zhang, L. ; Rosenbohm, A. ; Sijlmans, C. ; Aly, A. ; Mersmann, S. ; Sanjuan-Ruiz, I. ; Hübers, A. ; Messaddeq, N. ; Wagner, M. ; van Bakel, N. ; Boutillier, A.-L. ; Ludolph, A. ; Lagier-Tourenne, C. ; Böckers, T.DZNE* ; Dupuis, L. (Corresponding author) ; Storkebaum, E.

2019
Nature Publ. Group62203 London

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Please use a persistent id in citations: doi:10.1038/s41593-019-0498-9

Abstract: 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.

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

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Contributing Institute(s):

1. Translational protein biochemistry (AG Böckers)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2019

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Database coverage:
; BIOSIS Previews ; BIOSIS Reviews Reports And Meetings ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 30 ; JCR ; Nationallizenz ; SCOPUS ; Web of Science Core Collection

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Linked articles:

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Journal Article (Erratum/Correction) Picchiarelli, G. ; Demestre, M. ; Zuko, A. ; Been, M. ; Higelin, J. ; Dieterlé, S. ; Goy, M.-A. ; Mallik, M. ; Sellier, C. ; Scekic-Zahirovic, J.Extern* ; Zhang, L. ; Rosenbohm, A. ; Sijlmans, C. ; Aly, A. ; Mersmann, S. ; Sanjuan-Ruiz, I. ; Hübers, A. ; Messaddeq, N. ; Wagner, M. ; van Bakel, N. ; Boutillier, A.-L. ; Ludolph, A.Extern* ; Lagier-Tourenne, C. ; Boeckers, T. M.DZNE* ; Dupuis, L. ; Storkebaum, E.
Author Correction: FUS-mediated regulation of acetylcholine receptor transcription at neuromuscular junctions is compromised in amyotrophic lateral sclerosis.
Nature neuroscience 29(8), 2049 - 2050 (2026) [10.1038/s41593-026-02396-9]2026   Files BibTeX | EndNote: XML, Text | RIS

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