Enzymatic Activity of the Scaffold Protein Rapsyn for Synapse Formation

Li, Lei; Cao, Ya; Wu, Haitao; Ye, Xinchun; Zhu, Zhihui; Xing, Guanglin; Shen, Chengyong; Barik, Arnab; Zhang, Bin; Xie, Xiaoling; Zhi, Wenbo; Gan, Lin; Su, Huabo; Xiong, Wen-Cheng; Mei, Lin

doi:10.1016/j.neuron.2016.10.023

Cited by 72 publications

(88 citation statements)

References 84 publications

(111 reference statements)

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“…The RING‐H2 domain of rapsyn has been reported to function as an E3 ligase, covalently tagging AChRs with the ubiquitin‐like protein Nedd8, and thereby protecting AChRs from ubiquitin‐mediated degradation (Li et al . ). Rapsyn can also bind to β‐dystroglycan (Cartaud et al .…”

Section: Discussionmentioning

confidence: 97%

“…In turn, rapsyn binds phosphorylated AChRs and stabilizes the endplate (Apel et al 1997;Gervásio & Phillips, 2005;Gervásio et al 2007;Borges et al 2008;Brockhausen et al 2008;Luo et al 2008;Ghazanfari et al 2011). The RING-H2 domain of rapsyn has been reported to function as an E3 ligase, covalently tagging AChRs with the ubiquitin-like protein Nedd8, and thereby protecting AChRs from ubiquitin-mediated degradation (Li et al 2016). Rapsyn can also bind to β-dystroglycan (Cartaud et al 1998;Bartoli et al 2001).…”

Section: Discussionmentioning

confidence: 99%

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Muscle specific kinase protects dystrophic mdx mouse muscles from eccentric contraction‐induced loss of force‐producing capacity

Trajanovska

Ban

Huang

et al. 2019

The Journal of Physiology

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Key points Adeno‐associated viral vector was used to elevate the expression of muscle specific kinase (MuSK) and rapsyn (a cytoplasmic MuSK effector protein) in the tibialis anterior muscle of wild‐type and dystrophic (mdx) mice. In mdx mice, enhanced expression of either MuSK or rapsyn ameliorated the acute loss of muscle force associated with strain injury. Increases in sarcolemmal immunolabelling for utrophin and β‐dystroglycan suggest a mechanism for the protective effect of MuSK in mdx muscles. MuSK also caused subtle changes to the structure and function of the neuromuscular junction, suggesting novel roles for MuSK in muscle physiology and pathophysiology. Abstract Muscle specific kinase (MuSK) has a well‐defined role in stabilizing the developing mammalian neuromuscular junction, but MuSK might also be protective in some neuromuscular diseases. In the dystrophin‐deficient mdx mouse model of Duchenne muscular dystrophy, limb muscles are especially fragile. We injected the tibialis anterior muscle of 8‐week‐old mdx and wild‐type (C57BL10) mice with adeno‐associated viral vectors encoding either MuSK or rapsyn (a cytoplasmic MuSK effector protein) fused to green fluorescent protein (MuSK‐GFP and rapsyn‐GFP, respectively). Contralateral muscles injected with empty vector served as controls. One month later mice were anaesthetized with isoflurane and isometric force‐producing capacity was recorded from the distal tendon. MuSK‐GFP caused an unexpected decay in nerve‐evoked tetanic force, both in wild‐type and mdx muscles, without affecting contraction elicited by direct electrical stimulation of the muscle. Muscle fragility was probed by challenging muscles with a strain injury protocol consisting of a series of four strain‐producing eccentric contractions in vivo. When applied to muscles of mdx mice, eccentric contraction produced an acute 27% reduction in directly evoked muscle force output, affirming the susceptibility of mdx muscles to strain injury. mdx muscles overexpressing MuSK‐GFP or rapsyn‐GFP exhibited significantly milder force deficits after the eccentric contraction challenge (15% and 14%, respectively). The protective effect of MuSK‐GFP in muscles of mdx mice was associated with increased immunolabelling for utrophin and β‐dystroglycan in the sarcolemma. Elevating the expression of MuSK or rapsyn revealed several distinct synaptic and extrasynaptic effects, suggesting novel roles for MuSK signalling in muscle physiology and pathophysiology.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Muscle specific kinase protects dystrophic mdx mouse muscles from eccentric contraction‐induced loss of force‐producing capacity

Trajanovska

Ban

Huang

et al. 2019

The Journal of Physiology

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“…Through its multiple interaction domains, rapsyn also recruits protein kinase A and suppresses the activity of calcium‐activated proteases in the vicinity of the AChR cluster . In addition, rapsyn functions as an E3 ligase, covalently tagging AChRs with Nedd8, a small ubiquitin‐like protein . This combination of actions slows the metabolic turnover of the clustered AChRs and helps recruit and sustain the very high density of AChRs within the functioning postsynaptic membrane.…”

Section: The Musk–rapsyn System At the Healthy Nmjmentioning

confidence: 99%

The mouse passive‐transfer model of MuSK myasthenia gravis: disrupted MuSK signaling causes synapse failure

Ghazanfari

Trajanovska

Morsch

et al. 2017

Annals of the New York Academy of Sciences

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While the majority of myasthenia gravis patients express antibodies targeting the acetylcholine receptor, the second most common cohort instead displays autoantibodies against muscle-specific kinase (MuSK). MuSK is a transmembrane tyrosine kinase found in the postsynaptic membrane of the neuromuscular junction. During development, MuSK serves as a signaling hub, coordinating the alignment of the pre- and postsynaptic components of the synapse. Adult mice that received repeated daily injections of IgG from anti-MuSK myasthenia gravis patients developed muscle weakness, associated with neuromuscular transmission failure. MuSK autoantibodies are predominantly of the IgG4 type. They suppress the kinase activity of MuSK and the phosphorylation of target proteins in the postsynaptic membrane. Loss of postsynaptic acetylcholine receptors is the primary cause of neuromuscular transmission failure. MuSK autoantibodies also disrupt the capacity of the motor nerve terminal to adaptively increase acetylcholine release in response to the reduced postsynaptic responsiveness to acetylcholine. The passive IgG transfer model of MuSK myasthenia gravis has been used to test candidate treatments. Pyridostigmine, a first-line cholinesterase inhibitor drug, exacerbated the disease process, while 3,4-diaminopyridine and albuterol were found to be beneficial in this mouse model.

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“…Downstream mechanisms of MuSK are not well understood; nevertheless, AChR clustering requires rapsyn, an adaptor protein that is thought to bridge the AChR with the cytoskeleton . Recent data indicate that rapsyn is an E3 ligase that modifies proteins by neddylation …”

Section: Agrin/lrp4/musk Signalingmentioning

confidence: 99%

Agrin and LRP4 antibodies as new biomarkers of myasthenia gravis

Yan

Xing

Xiong

et al. 2018

Annals of the New York Academy of Sciences

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Myasthenia gravis (MG) is a common disorder that affects the neuromuscular junction. It is caused by antibodies against acetylcholine receptor and muscle-specific tyrosine kinase; however, some MG patients do not have antibodies against either of the proteins. Recent studies have revealed antibodies against agrin and its receptor LRP4-both critical for neuromuscular junction formation and maintenance-in MG patients from various populations. Results from experimental autoimmune MG animal models indicate that anti-LRP4 antibodies are causal to MG. Clinical studies have begun to reveal the significance of the new biomarkers. With their identification, MG appears to be a complex disease entity that can be classified into different subtypes with different etiology, each with unique symptoms. Future systematic studies of large cohorts of well-diagnosed MG patients are needed to determine whether each subtype of patients would respond to different therapeutic strategies. Results should contribute to the goal of precision medicine for MG patients. Anti-agrin and anti-LRP4 antibodies are also detectable in some patients with amyotrophic lateral sclerosis or Lou Gehrig's disease; however, whether they are a cause or response to the disorder remains unclear.

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Enzymatic Activity of the Scaffold Protein Rapsyn for Synapse Formation

Cited by 72 publications

References 84 publications

Muscle specific kinase protects dystrophic mdx mouse muscles from eccentric contraction‐induced loss of force‐producing capacity

Muscle specific kinase protects dystrophic mdx mouse muscles from eccentric contraction‐induced loss of force‐producing capacity

The mouse passive‐transfer model of MuSK myasthenia gravis: disrupted MuSK signaling causes synapse failure

Agrin and LRP4 antibodies as new biomarkers of myasthenia gravis

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