Dynein disruption perturbs post-synaptic components and contributes to impaired MuSK clustering at the NMJ: implication in ALS.
The neuromuscular junction (NMJ) allows the transformation of a neuronal message into a mechanical force by muscle contraction and is the target of several neuromuscular disorders. While the neuronal side is under extensive research, the muscle appeared recently to have a growing role in the formation and integrity of the neuromuscular junction. We used an in vitro model of mature myofibers to study the role of dynein on major postsynaptic proteins. We found that dynein affects the expression and the clustering of acetylcholine receptors (AChRs), muscle specific tyrosine kinase (MuSK) and Rapsyn. We also show that myofibers with dynein impairment or from an amyotrophic lateral sclerosis (ALS) model (SOD1(G93A)) show similar defects in myofiber formation and agrin-induced AChR clustering suggesting a role for dynein impairment in ALS progression. Finally, we found that dynein can affect MuSK traffic through the endosomal pathway. Collectively, our studies show that defects in dynein can lead to impairment of muscle NMJ components' expression and clustering. We propose that NMJ defects could happen via defective MuSK traffic and that this could be one of the pathological features involved in neurodegeneration such as ALS.
Myology Research Center, UM76-INSERM U974-CNRS FRE 3617 Sorbonne Universités, UPMC Université Paris 06, Paris, France.
Valérie
V
Vilmont
Myology Research Center, UM76-INSERM U974-CNRS FRE 3617 Sorbonne Universités, UPMC Université Paris 06, Paris, France.
Bruno
B
Cadot
Myology Research Center, UM76-INSERM U974-CNRS FRE 3617 Sorbonne Universités, UPMC Université Paris 06, Paris, France.
Elsa
E
Vezin
Myology Research Center, UM76-INSERM U974-CNRS FRE 3617 Sorbonne Universités, UPMC Université Paris 06, Paris, France.
Fabien
F
Le Grand
Myology Research Center, UM76-INSERM U974-CNRS FRE 3617 Sorbonne Universités, UPMC Université Paris 06, Paris, France.|Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
Edgar R
ER
Gomes
D018171:Agrin / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004398:Dyneins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D009469:Neuromuscular Junction / Q000378:metabolism*; D015739:Nocodazole / Q000494:pharmacology; D052999:Quinazolinones / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011950:Receptors, Cholinergic / Q000378:metabolism; D000072105:Superoxide Dismutase-1 / Q000235:genetics / Q000378:metabolism
D018171:Agrin; D009124:Muscle Proteins; D052999:Quinazolinones; D034741:RNA, Small Interfering; D011950:Receptors, Cholinergic; C000595851:ciliobrevin D; C051609:peripheral membrane protein 43K; C000606291:Sod1 protein, mouse; D000072105:Superoxide Dismutase-1; C511695:MuSK protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D004398:Dyneins; D015739:Nocodazole