Abstract
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 (SOD1G93A) 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.
Highlights
The neuromuscular junction (NMJ) is a structure at the basis of synapse-dependent muscle contraction where the motor neuron interacts with the muscle[1,2]
Because the dynein complex has been described as an important protagonist of muscle development[29,30,31], we investigated if muscle dynein is involved in NMJ formation and in amyotrophic lateral sclerosis (ALS)
We used neural agrin known to induce acetylcholine receptor (AChR) clustering, a post-synaptic receptor expressed at NMJs in vivo[33,34,35,36]
Summary
Dynein is involved in AChR cluster formation and maintenance. We differentiated myofibers from primary myoblasts isolated from WT or histone2B-GFP (H2B-GFP) P7 mice as previously described[32]. These results show that myofibers with dynein impairment or from an ALS model (SOD1G93A) show similar defects on myofiber formation and agrin-induced AChR clusters Because these SOD1G93A show same myofiber differentiation defects as in shDHC at late differentiation (Day 9), it could be possible that the defective phenotypes observed for post-synaptic features like clusters of MuSK and active MuSK are either i) subsequent to an underlying myofiber differentiation impairment or ii) already triggered by dynein dysfunction at earlier time points (Day 6) and enhanced in these mice due to underlying muscle differentiation defects linked to dynein dysfunction. Our data suggests a role of dynein in MuSK recycling and transport which can probably lead to gradual Rapsyn destabilization from the NMJ and further AChR cluster loss like seen in SOD1G93A mice Such events occurring at the post-synapse replace the muscle as a primary target for ALS treatment. Whether MuSK defective trafficking can be enhanced due to other impaired processes such as delayed differentiation disrupted in conditions of dynein dysfunction still needs to be investigated and the role of denervation in vivo needs further studies
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