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

Picchiarelli, Gina; Demestre, Maria; Zuko, Amila; Been, Marije; Higelin, Julia; Dieterlé, Stéphane; Goy, Marc-Antoine; Mallik, Moushami; Sellier, Chantal; Scekic‐Zahirovic, Jelena; Zhang, Li; Rosenbohm, Angela; Sijlmans, Céline; Aly, Amr; Mersmann, Sina; Sanjuan-Ruiz, Inmaculada; Hübers, Annemarie; Messaddeq, Nadia; Wagner, Marina; Bakel, Nick van; Boutillier, Anne‐Laurence; Ludolph, Albert C.; Lagier‐Tourenne, Clotilde; Boeckers, Tobias M.; Dupuis, Luc; Storkebaum, Erik

doi:10.1038/s41593-019-0498-9

Cited by 98 publications

(118 citation statements)

References 46 publications

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“…Finally, in motor neuron/myotube co-cultures, ALS-mutant FUS was intrinsically toxic to both motor neurons and myotubes. Altogether, these data show that FUS plays a key role in regulating selective expression of AChR genes in subsynaptic nuclei and indicate that intrinsic toxicity of ALS-mutant FUS in the muscle may be critical for ALS [115]. FUS is also involved in SMA, through a direct interaction between FUS and SMN through the U1-snRNP.…”

Section: Fusmentioning

confidence: 70%

“…FUS also exerts critical roles in neuromuscular junction development. Animal models of FUS-ALS show alteration of synaptic transmission and modification of NMJ numbers and size [110][111][112][113][114], and we recently demonstrated that FUS is required for the post-synaptic development of the NMJ [115]. Indeed, both knock-in and knock-out mice for Fus developed NMJ morphology defects.…”

Section: Fusmentioning

confidence: 99%

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Role of RNA Binding Proteins with prion-like domains in muscle and neuromuscular diseases

Picchiarelli¹,

Dupuis²

2020

CST

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A number of neuromuscular and muscular diseases, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and several myopathies, are associated to mutations in related RNA-binding proteins (RBPs), including TDP-43, FUS, MATR3 or hnRNPA1/B2. These proteins harbor similar modular primary sequence with RNA binding motifs and low complexity domains, that enables them to phase separate and create liquid microdomains. These RBPs have been shown to critically regulate multiple events of RNA lifecycle, including transcriptional events, splicing and RNA trafficking and sequestration. Here, we review the roles of these disease-related RBPs in muscle and motor neurons, and how their dysfunction in these cell types might contribute to disease.

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Section: Fusmentioning

confidence: 70%

Section: Fusmentioning

confidence: 99%

Role of RNA Binding Proteins with prion-like domains in muscle and neuromuscular diseases

Picchiarelli¹,

Dupuis²

2020

CST

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“…Furthermore, the replacement of murine FUS with a mutated human form activates an integrated stress response and inhibit local intra-axonal protein synthesis in hippocampal neurons and sciatic nerves, resulting in synaptic dysfunction (López-Erauskin et al, 2018). A recent study found that transcription of an acetylcholine receptor is compromised in FUS-mediated ALS, thus supporting the idea that FUS affects gene expression (Picchiarelli et al, 2019).…”

Section: Discussionmentioning

confidence: 62%

An ALS-associated mutation in human FUS reduces neurotransmission fromC. elegansmotor neurons to muscles

Markert

Skoruppa

et al. 2019

Preprint

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Amytrophic lateral sclerosis (ALS) is a neurodegenerative disorder that has been associated with multiple genetic lesions, including mutations in the gene FUS (Fused in Sarcoma), an RNA/DNA-binding protein. Expression of the ALS-associated human FUS in C. elegans results in mislocalization and aggregation of FUS outside the nucleus, and leads to impaired neuromuscular behaviors. However, the mechanisms by which mutant FUS disrupts neuronal health and function remain partially understood. Here we investigated the impact of ALS-associated FUS on motor neuron health using correlative light and electron microscopy, electron tomography, and electrophysiology. Expression of ALS-associated FUS impairs synaptic vesicle docking at neuromuscular junctions, and leads to the emergence of a population of large and electron-dense filament-filled endosomes. Electrophysiological recording of neuromuscular transmission revealed reduced transmission from motor neurons to muscles. Together, these results suggest a potential direct or indirect role of human FUS in the organization of synaptic vesicles, and reduced transmission from motor neurons to muscles. Summary statement An ALS-associated mutation in a trafficking protein disrupts the organization of the C. elegans neuromuscular junction.

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“…On the other hand, selective reduction of mutant SOD1 expression in skeletal muscle of mutant SOD1 transgenic mice did not affect their disease course, neither did increasing muscle fiber number and diameter by follistatin expression [27,28]. Intriguingly, a recent study reported that ALS-mutant FUS is intrinsically toxic to both motor neurons and muscle cells, and toxicity in muscle may be attributable to defective FUS-mediated transcriptional regulation of acetylcholine receptor subunit genes [29]. While this and other studies in FUS-ALS mouse models indicate that a gain-of-toxic-function of ALS-mutant FUS is required to cause motor neuron degeneration [30][31][32] Interestingly, FGF signaling has previously been implicated in ALS pathogenesis, through retrograde FGF signaling from muscle to motor neuron [33].…”

Section: Discussionmentioning

confidence: 95%

TheDrosophila FUSorthologcabezapromotes adult founder myoblast selection by Xrp1-dependent regulation of FGF signaling

Catinozzi

Mallik

Frickenhaus

et al. 2020

Preprint

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AbstractThe number of adult myofibers in Drosophila is determined by the number of founder myoblasts selected from a myoblast pool, a process governed by fibroblast growth factor (FGF) signaling. Here, we show that loss of cabeza (caz) function results in a reduced number of adult founder myoblasts, leading to a reduced number and misorientation of adult dorsal abdominal muscles. Genetic experiments revealed that loss of caz function in both adult myoblasts and neurons contributes to caz mutant muscle phenotypes. Selective overexpression of the FGF receptor Htl or the FGF receptor-specific signaling molecule Stumps in adult myoblasts partially rescued caz mutant muscle phenotypes, and Stumps levels were reduced in caz mutant founder myoblasts, indicating FGF pathway deregulation. In both adult myoblasts and neurons, caz mutant muscle phenotypes were mediated by increased expression levels of Xrp1, a DNA-binding protein involved in gene expression regulation. Xrp1-induced phenotypes were dependent on the DNA-binding capacity of its AT-hook motif, and increased Xrp1 levels in founder myoblasts reduced Stumps expression. Thus, control of Xrp1 expression by Caz is required for regulation of Stumps expression in founder myoblasts, resulting in correct founder myoblast selection.Author SummarySkeletal muscles mediate movement, and therefore, proper structure and function of skeletal muscles is required for respiration, locomotion, and posture. Adult muscles arise from fusion of muscle precursor cells during development. In the fruit fly Drosophila melanogaster, muscle precursor cells come in two flavors: founder cells and fusion-competent cells. The number of founder cells selected during development corresponds to the number of adult muscles formed. Here, we report that inactivation of the Drosophila caz gene results in muscle developmental defects. Loss of caz function in both muscle precursor cells and the nerve cells that innervate muscles contributes to the muscle developmental defect. At the molecular level, loss of caz function leads to increased levels of Xrp1. Xrp1 regulates the expression of many other genes, including genes that produce components of the FGF signaling pathway, which is known to be involved in founder cell selection. In all, we uncovered a novel molecular mechanism that regulates founder cell selection during muscle development.

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

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Cited by 98 publications

References 46 publications

Role of RNA Binding Proteins with prion-like domains in muscle and neuromuscular diseases

Role of RNA Binding Proteins with prion-like domains in muscle and neuromuscular diseases

An ALS-associated mutation in human FUS reduces neurotransmission fromC. elegansmotor neurons to muscles

TheDrosophila FUSorthologcabezapromotes adult founder myoblast selection by Xrp1-dependent regulation of FGF signaling

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