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Congenital Myasthenic Syndromes (CMSs) are rare inherited diseases of the neuromuscular junction characterized by muscle weakness. CMSs with acetylcholinesterase deficiency are due to pathogenic variants in COLQ, a collagen that anchors the enzyme at the synapse. The two COLQ N-terminal domains have been characterized as being biochemical and functional. They are responsible for the structure of the protein in the triple helix and the association of COLQ with acetylcholinesterase. To deepen the analysis of the distal C-terminal peptide properties and understand the CMSs associated to pathogenic variants in this domain, we have analyzed the case of a 32 year old male patient bearing a homozygote splice site variant c.1281 C > T that changes the sequence of the last 28 aa in COLQ. Using COS cell and mouse muscle cell expression, we show that the COLQ variant does not impair the formation of the collagen triple helix in these cells, nor its association with acetylcholinesterase, and that the hetero-oligomers are secreted. However, the interaction of COLQ variant with LRP4, a signaling hub at the neuromuscular junction, is decreased by 44% as demonstrated by in vitro biochemical methods. In addition, an increase in all acetylcholine receptor subunit mRNA levels is observed in muscle cells derived from the patient iPSC. All these approaches point to pathophysiological mechanisms essentially characterized by a decrease in signaling and the presence of immature acetylcholine receptors. [ABSTRACT FROM AUTHOR]

The receptor tyrosine kinase MuSK, its co-receptor Lrp4 and the Agrin ligand constitute a signaling pathway that is crucial in axial muscle for neuromuscular synapse development, yet whether this pathway functions similarly in appendicular muscle is unclear. Here, using the larval zebrafish pectoral fin, equivalent to tetrapod forelimbs, we show that, similar to axial muscle, developing appendicular muscles form aneural acetylcholine receptor (AChR) clusters prior to innervation. As motor axons arrive, neural AChR clusters form, eventually leading to functional synapses in a MuSK-dependent manner.We find that loss of Agrin or Lrp4 function, which abolishes synaptic AChR clusters in axial muscle, results in enlarged presynaptic nerve regions and progressively expanding appendicular AChRclusters,mimicking the consequences of motoneuron ablation. Moreover, musk depletion in lrp4 mutants partially restores synaptic AChR patterning. Combined, our results provide compelling evidence that, in addition to the canonical pathway in which Agrin/Lrp4 stimulates MuSK activity, Agrin/Lrp4 signaling in appendicular muscle constrains MuSK-dependent neuromuscular synapse organization. Thus, we reveal a previously unappreciated role for Agrin/Lrp4 signaling, thereby highlighting distinct differences between axial and appendicular synapse development. [ABSTRACT FROM AUTHOR]

Background: The neuromuscular junction (NMJ) is a peripheral synapse critical to muscle contraction. Like acetylcholine receptors (AChRs), many essential proteins of NMJ are extremely concentrated at the postjunctional membrane. However, the mechanisms of synapse-specific concentration are not well understood; furthermore, it is unclear whether signaling molecules critical to NMJ formation and maintenance are also locally transcribed. Results: We studied the β-gal activity encoded by a lacZ cassette driven by the promoter of the Lrp4 gene. As reported for Lrp4 mRNA, β-gal was in the central region in embryonic muscles and at the NMJ after its formation. However, β-gal was no longer in the central areas of muscle fibers in Lrp4 or MuSK mutant mice, indicating a requirement of Lrp4/MuSK signaling. This phenotype could be rescued by transgenic expression of LRP4 with a transmembrane domain but not soluble ECD in Lrp4 mutant mice. β-gal and AChR clusters were distributed in a broader region in lacZ/ECD than that of heterozygous lacZ/+ mice, indicating an important role of the transmembrane domain in Lrp4 signaling. Synaptic β-gal activity became diffused after denervation or treatment with µ-conotoxin, despite its mRNA was increased, indicating synaptic Lrp4 mRNA enrichment requires muscle activity. β-gal was also diffused in aged mice but became re-concentrated after muscle stimulation. Finally, Lrp4 mRNA was increased in C2C12 myotubes by Wnt ligands in a manner that could be inhibited by RKI-1447, an inhibitor of ROCK in Wnt non-canonical signaling. Injecting RKI-1447 into muscles of adult mice diminished Lrp4 synaptic expression. Conclusions: This study demonstrates that synapse-specific enrichment of Lrp4 mRNA requires a coordinated interaction between Lrp4/MuSK signaling, muscle activity, and Wnt non-canonical signaling. Thus, the study provides a new mechanism for Lrp4 mRNA enrichment. It also provides a potential target for the treatment of NMJ aging and other NMJ-related diseases. [ABSTRACT FROM AUTHOR]

Agrin is a crucial factor that induces postsynaptic differentiation at neuromuscular junctions (NMJs), but how secreted agrin is locally deposited in the context of extracellular matrix (ECM) environment and its function in presynaptic differentiation remain largely unclear. Here, we report that the proteolytic activity of neuronal membranetype 1 matrix metalloproteinase (MT1-MMP; also known as MMP14) facilitates agrin deposition and signaling during presynaptic development at NMJs. Firstly, agrin deposition along axons exhibits a time-dependent increase in cultured neurons that requires MMPmediated focal ECM degradation. Next, local agrin stimulation induces the clustering of mitochondria and synaptic vesicles, two well-known presynaptic markers, and regulates vesicular trafficking and surface insertion of MT1-MMP. MMP inhibitor or MT1-MMP knockdown suppresses agrin-induced presynaptic differentiation, which can be rescued by treatment with the ectodomain of lowdensity lipoprotein receptor-related protein 4 (Lrp4). Finally, neuronal MT1-MMP knockdown inhibits agrin deposition and nerve-induced acetylcholine receptor clustering in nerve-muscle co-cultures and affects synaptic structures at Xenopus NMJs in vivo. Collectively, our results demonstrate a previously unappreciated role of agrin, as well as dual functions of neuronal MT1-MMP proteolytic activity in orchestrating agrin deposition and signaling, in presynaptic development. [ABSTRACT FROM AUTHOR]

Myasthenia gravis (MG) is a disease of the postsynaptic neuromuscular junction (NMJ) where nicotinic acetylcholine (ACh) receptors (AChRs) are targeted by autoantibodies. Search for other pathogenic antigens has detected the antibodies against muscle-specific tyrosine kinase (MuSK) and low-density lipoprotein-related protein 4 (Lrp4), both causing pre- and post-synaptic impairments. Agrin is also suspected as a fourth pathogen. In a complex NMJ organization centering on MuSK: (1) the Wnt non-canonical pathway through the Wnt-Lrp4-MuSK cysteine-rich domain (CRD)-Dishevelled (Dvl, scaffold protein) signaling acts to form AChR prepatterning with axonal guidance; (2) the neural agrin-Lrp4-MuSK (Ig1/2 domains) signaling acts to form rapsyn-anchored AChR clusters at the innervated stage of muscle; (3) adaptor protein Dok-7 acts on MuSK activation for AChR clustering from "inside" and also on cytoskeleton to stabilize AChR clusters by the downstream effector Sorbs1/2; (4) the trans-synaptic retrograde signaling contributes to the presynaptic organization via : (i) Wnt-MuSK CRD-Dvl-β catenin-Slit 2 pathway; (ii) Lrp4; and (iii) laminins. The presynaptic Ca2+ homeostasis conditioning ACh release is modified by autoreceptors such as M1-type muscarinic AChR and A2A adenosine receptors. The post-synaptic structure is stabilized by: (i) laminin-network including the muscle-derived agrin; (ii) the extracellular matrix proteins (including collagen Q/perlecan and biglycan which link to MuSK Ig1 domain and CRD); and (iii) the dystrophin-associated glycoprotein complex. The study on MuSK ectodomains (Ig1/2 domains and CRD) recognized by antibodies suggested that the MuSK antibodies were pathologically heterogeneous due to their binding to multiple functional domains. Focussing one of the matrix proteins, biglycan which functions in the manner similar to collagen Q, our antibody assay showed the negative result in MG patients. However, the synaptic stability may be impaired by antibodies against MuSK ectodomains because of the linkage of biglycan with MuSK Ig1 domain and CRD. The pathogenic diversity of MG is discussed based on NMJ signaling molecules. [ABSTRACT FROM AUTHOR]

During aging, acetylcholine receptor (AChR) clusters become fragmented and denervated at the neuromuscular junction (NMJ). Underpinning molecular mechanisms are not well understood. We showed that LRP4, a receptor for agrin and critical for NMJ formation and maintenance, was reduced at protein level in aged mice, which was associated with decreased MuSK tyrosine phosphorylation, suggesting compromised agrin-LRP4-MuSK signaling in aged muscles. Transgenic expression of LRP4 in muscles alleviated AChR fragmentation and denervation and improved neuromuscular transmission in aged mice. LRP4 ubiquitination was augmented in aged muscles, suggesting increased LRP4 degradation as a mechanism for reduced LRP4. We found that sarcoglycan α (SGα) interacted with LRP4 and delayed LRP4 degradation in cotransfected cells. AAV9-mediated expression of SGα in muscles mitigated AChR fragmentation and denervation and improved neuromuscular transmission in aged mice. These observations support a model where compromised agrin- LRP4-MuSK signaling serves as a pathological mechanism of age-related NMJ decline and identify a novel function of SGa in stabilizing LRP4 for NMJ stability in aged mice. [ABSTRACT FROM AUTHOR]

Background and purpose: Myasthenia gravis (MG) is an autoimmune disorder characterized by fatigable muscle weakness due to antibody‐mediated impairment of neuromuscular transmission. The aim of this study was to investigate the incidence and prevalence of MG in Latvia, and to characterize this population by well‐established clinical parameters such as age at onset, presence of associated antibodies and thymus pathology. Methods: All prevalent cases on 1 January 2015 and cases of patients newly presenting with MG symptoms from 1 January 2010 to 31 December 2014 were selected from the database of the Neuromuscular Disease Clinic of Pauls Stradins Clinical University Hospital and Children's Clinical University Hospital. Crude rates were calculated based on population data. These were directly age‐standardized to the European and World Health Organization world standard populations. The analysis of clinical characteristics was carried out in a cohort of patients who had undergone a complete set of electrophysiological, serological and radiological investigations (n = 153; 68%). Results: During the study period 99 incident and 226 prevalent cases were identified. The total crude MG incidence was 9.7 per million person‐years. The prevalence of MG on 1 January 2015 was 113.8 per million. 54.2% of patients tested positive for acetylcholine receptor antibodies, 7.8% for muscle specific kinase antibodies and 1.3% for lipoprotein related protein 4 antibodies. Conclusions: This is the first study of MG in Latvia and the second population‐based study of MG in Eastern Europe. Our epidemiological results are similar to those in some other European and Northern American countries, and show high prevalence and increasing incidence of late‐onset MG. [ABSTRACT FROM AUTHOR]

The neuromuscular synapse is a relatively large synapse with hundreds of active zones in presynaptic motor nerve terminals and more than ten million acetylcholine receptors (AChRs) in the postsynaptic membrane. The enrichment of proteins in presynaptic and postsynaptic membranes ensures a rapid, robust, and reliable synaptic transmission. Over fifty years ago, classic studies of the neuromuscular synapse led to a comprehensive understanding of how a synapse looks and works, but these landmark studies did not reveal the molecular mechanisms responsible for building and maintaining a synapse. During the past two-dozen years, the critical molecular players, responsible for assembling the specialized postsynaptic membrane and regulating nerve terminal differentiation, have begun to be identified and their mechanism of action better understood. Here, we describe and discuss five of these key molecular players, paying heed to their discovery as well as describing their currently understood mechanisms of action. In addition, we discuss the important gaps that remain to better understand how these proteins act to control synaptic differentiation and maintenance. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

Introduction: In this study we determined the frequencies of antibodies (Abs) directed against muscle-specific kinase (MuSK) and lipoprotein receptor-related protein 4 (LRP4) in the sera of a South African cohort with acetylcholine receptor (AChR)-antibody-negative generalized MG and determined outcomes to therapies.Methods: Sera negative by commercial AChR radioimmunoassay (RIA) were tested by MuSK RIA (n = 30; 2006-2012) and AChR, MuSK, and LRP4 RIA with or without cell-based assays (CBA) (n = 53; 2012-2015).Results: AChR-Abs were detected in 4 of 53 and MuSK-Abs in 20 of 83 (24%) cases. Thirty-six of 53 (68%) were triple seronegative (triple-SNMG) for MuSK, AChR, and LRP4-Abs. When compared with triple-SNMG, individuals with MuSK-MG had a younger onset age (P = 0.008), a greater likelihood of African genetic ancestry (P = 0.008), and 4-fold higher odds of reaching MGFA grade IVB/V (P = 0.018), but were also 9-fold more likely to reach at least minimal manifestations status after ≥12 months of therapy (P = 0.003).Conclusions: Individuals with African genetic ancestry and severe bulbar/respiratory AChR-Ab-negative MG are likely to have MuSK-MG, but most respond favorably to maintenance immunotherapies. Muscle Nerve 54: 1023-1029, 2016. [ABSTRACT FROM AUTHOR]

Motor axons approach muscles that are prepatterned in the prospective synaptic region. In mice, prepatterning of acetylcholine receptors requires Lrp4, a LDLR family member, and MuSK, a receptor tyrosine kinase. Lrp4 can bind and stimulate MuSK, strongly suggesting that association between Lrp4 and MuSK, independent of additional ligands, initiates prepatterning in mice. In zebrafish, Wnts, which bind the Frizzled (Fz)-like domain in MuSK, are required for prepatterning, suggesting that Wnts may contribute to prepatterning and neuromuscular development in mammals. We show that prepatterning in mice requires Lrp4 but not the MuSK Fz-like domain. In contrast, prepatterning in zebrafish requires the MuSK Fz-like domain but not Lrp4. Despite these differences, neuromuscular synapse formation in zebrafish and mice share similar mechanisms, requiring Lrp4, MuSK, and neuronal Agrin but not the MuSK Fz-like domain or Wnt production from muscle. Our findings demonstrate that evolutionary divergent mechanisms establish muscle prepatterning in zebrafish and mice. [ABSTRACT FROM AUTHOR]

Myasthenia gravis (MG) is the archetypic disorder of both the neuromuscular junction and autoantibody-mediated disease. In most patients, IgG1-dominant antibodies to acetylcholine receptors cause fatigable weakness of skeletal muscles. In the rest, a variable proportion possesses antibodies to muscle-specific tyrosine kinase while the remainder of seronegative MG is being explained through cell-based assays using a receptor-clustering technique and, to a lesser extent, proposed new antigenic targets. The incidence and prevalence of MG are increasing, particularly in the elderly. New treatments are being developed, and results from the randomised controlled trial of thymectomy in non-thymomatous MG, due for release in early 2016, will be of particular clinical value. To help navigate an evidence base of varying quality, practising clinicians may consult new MG guidelines in the fields of pregnancy, ocular and generalised MG (GMG). This review focuses on updates in epidemiology, immunology, therapeutic and clinical aspects of GMG in adults. [ABSTRACT FROM AUTHOR]

The increasing demand on diagnostic assays that are sensitive and specific for pathogenic antibodies, and the interest in identifying new antigens, prompted the development of cell-based assays for the detection of autoantibodies in myasthenia gravis and other autoimmune disorders. Cell-based assays were initially used to show that clustering the AChR improved the positivity in myasthenia gravis, and similar assays have now been applied to detection of antibodies to neuromuscular junction candidate proteins such as LRP4 and agrin. In addition cell-based assays have been used in the routine detection of antibodies to proteins expressed on the surface of neurons (NMDAR, LGI1, CASPR2, AMPAR, GABA-A/B, GlyR, and DPPX) and glia (AQP4, MOG). Here, we summarize the findings in myasthenia and discuss the advantages, disadvantages and controversial issues of using cell-based assays in the detection of these antibodies, and their relevance to the testing of preclinical models of disease. [ABSTRACT FROM AUTHOR]

LRP4 is a post-synaptic membrane protein that promotes acetylcholine (AChR) clustering on the crest of post-synaptic neuromuscular folds. Autoantibodies against LRP4 are suggested to account for myasthenia gravis (MG) patients negative for antibodies to AChR. To report a clinical experience with service-line LRP4-IgG cell-based testing in electrodiagnostically confirmed MG patients and controls. We identified all Mayo patients undergoing MG evaluations with send out LRP4-IgG antibody testing by cell-based assay, having clinical-electrodiagnostic (EDX) testing. To be included, muscle acetylcholine receptor binding (AChR-Bi) and muscle-specific tyrosine kinase (MuSK) antibodies had to be absent prior to LRP4-IgG testing. Follow-up AChR-Bi antibody testing was reviewed. Also tested for LRP4-IgGs were 119 healthy subjects. Identified were 25 generalized MG, 24 ocular MG, and 55 patients initially considered to have MG prior to negative EDX testing. No seronegative patients with EDX confirmed MG had LRP4-IgG positivity but five non-MG patients did: Guillain-Barre syndrome with fatigue (N = 1); multiple cranial neuropathies (N = 1); functional neurologic disorders (N = 3). Of healthy subjects, 4% (5/119) were LRP4-IgG positive (N = 5) or had a borderline result (N = 1). Of MG patients with repeat AChR-Bi testing, 40% (10/25) seroconverted (5 with ocular MG and 5 with generalized MG) (median AChR IgG value: 0.34 nmol/L, range 0.2–20.9 nmol/L, median followup 26 months, range 2–72 months). Clinical review of LRP4-IgG commercial cell-based testing suggests lack of diagnostic utility in seronegative EDX-confirmed MG. The clinical utility of LRP4-IgG testing is not substantiated in service line testing. In contrast, repeat testing for AChR-Bi antibodies is shown clinically useful. [ABSTRACT FROM AUTHOR]

The neuromuscular junction (NMJ) is a synapse between motor neurons and skeletal muscle fibers, and is critical for control of muscle contraction. Its formation requires neuronal agrin that acts by binding to LRP4 to stimulate MuSK. Mutations have been identified in agrin, MuSK, and LRP4 in patients with congenital myasthenic syndrome, and patients with myasthenia gravis develop antibodies against agrin, LRP4, and MuSK. However, it remains unclear whether the agrin signaling pathway is critical for NMJ maintenance because null mutation of any of the three genes is perinatal lethal. In this study, we generated imKO mice, a mutant strain whose LRP4 gene can be deleted in muscles by doxycycline (Dox) treatment. Ablation of the LRP4 gene in adult muscle enabled studies of its role in NMJ maintenance. We demonstrate that Dox treatment of P30 mice reduced muscle strength and compound muscle action potentials. AChR clusters became fragmented with diminished junctional folds and synaptic vesicles. The amplitude and frequency of miniature endplate potentials were reduced, indicating impaired neuromuscular transmission and providing cellular mechanisms of adult LRP4 deficiency. We showed that LRP4 ablation led to the loss of synaptic agrin and the 90 kDa fragments, which occurred ahead of other prejunctional and postjunctional components, suggesting that LRP4 may regulate the stability of synaptic agrin. These observations demonstrate that LRP4 is essential for maintaining the structural and functional integrity of the NMJ and that loss of muscle LRP4 in adulthood alone is sufficient to cause myasthenic symptoms. [ABSTRACT FROM AUTHOR]

Abstract: MuSK (muscle-specific kinase) is a receptor tyrosine kinase that plays a central signaling role in the formation of neuromuscular junctions (NMJs). MuSK is activated in a complex spatio-temporal manner to cluster acetylcholine receptors on the postsynaptic (muscle) side of the synapse and to induce differentiation of the nerve terminal on the presynaptic side. The ligand for MuSK is LRP4 (low-density lipoprotein receptor-related protein-4), a transmembrane protein in muscle, whose binding affinity for MuSK is potentiated by agrin, a neuronally derived heparan-sulfate proteoglycan. In addition, Dok7, a cytoplasmic adaptor protein, is also required for MuSK activation in vivo. This review focuses on the physical interplay between these proteins and MuSK for activation and downstream signaling, which culminates in NMJ formation. This article is part of a Special Issue entitled: Emerging recognition and activation mechanisms of receptor tyrosine kinases. [Copyright &y& Elsevier]

Abstract: Myasthenia gravis is caused by antibodies to the acetylcholine receptor, muscle-specific kinase, low-density lipoprotein receptor-related protein 4, or possibly yet unidentified antibodies. The mechanisms by which these antibodies interfere with the function of postsynaptic proteins include complement activation, antigenic modulation by crosslinking of the target proteins, competition with ligand binding sites, or steric hindrance which inhibits conformational changes or binding to associated proteins. Screening for auto-antibodies to different postsynaptic targets, and also for low-affinity antibodies, is contributing to a more accurate diagnosis of MG patients. Further studies into the specific pathophysiological pathways of the several MG subforms might help to develop new, more antigen specific, therapies. [Copyright &y& Elsevier]

Abstract: Myasthenia gravis (MG) is the most common immune-mediated disorder of the neuromuscular junction with a prevalence of 200–300/million population and its study has established paradigms for exploring other antibody-mediated diseases. Most MG patients (~85%) have autoantibodies against the muscle acetylcholine receptor (AChR-MG), whereas about 6% of MG patients have autoantibodies against the muscle specific kinase (MuSK-MG). Until recently no autoantibodies could be detected in the remaining patients (seronegative MG). Probably, the most sensitive assays for the detection of the autoantibodies in MG sera have been the radioimmunoprecipitation assays (RIPA) for both types of MG. However, with recent novel methods, not yet used routinely, it has been shown that the “seronegative” MG group includes patients with low levels of autoantibodies or of low affinity, against the known autoantigens, or even with antibodies to recently identified autoantigens. Since MG is heterogeneous in terms of pathophysiology, depending on the autoantigen targeted and on other factors (e.g. presence of thymoma), the serological tests are crucial in verifying the initial clinical diagnosis, whereas frequent measurement of autoantibody levels is important in monitoring the course of the disease and the efficacy of treatment. In addition, in AChR-MG, autoantibodies against the muscle proteins titin and ryanodin receptor have been identified; these antibodies are useful for the classification of MG, indicating the concomitant presence of thymoma, and as prognostic markers. [Copyright &y& Elsevier]

Around 80% of myasthenia gravis patients have antibodies against the acetylcholine receptor, and 0-60% of the remaining patients have antibodies against the muscle-specific tyrosine kinase, MuSK. Another recently identified antigen is low-density lipoprotein receptor-related protein 4 (Lrp4). To improve the existing assays and widen the search for new antigenic targets, we have employed cell-based assays in which candidate target proteins are expressed on the cell surface of transfected cells and probed with patient sera. These assays, combined with use of myotube cultures to explore the effects of the antibodies, enable us to begin to identify new antigenic targets and test antibody pathogenicity in vitro. [ABSTRACT FROM AUTHOR]

Simple Summary: Schwann cells (SCs) are the primary glial cells in the peripheral nervous system and play an indispensable role in peripheral nerve regeneration. A recent study indicated the potential involvement of low-density lipoprotein receptor-related protein 4 (Lrp4) in axonal regeneration in larval zebrafish. However, whether Lrp4 participates in nerve regeneration in mammals remains unknown. Herein, we constructed conditional knockout (cKO) mice in which Lrp4 was specifically deleted in SCs under the control of the Dhh-cre promoter. We found that the peripheral nerve regeneration in cKO mice was more robust than that in control mice. Assessment of SC proliferation via BrdU staining revealed significantly increased cell numbers in the cKO mice. Furthermore, as a master transcription factor participating in the onset of myelination, Krox-20 was dramatically downregulated in the injured nerves of the cKO group compared with the control group nerves. The enhanced demyelination speed in cKO mice was confirmed by electron microscopy. Altogether, these results suggest that Krox-20 downregulation in mutant mice leads to SC proliferation upon injury and that SCs can remove myelin debris, thereby promoting nerve regeneration. Low-density lipoprotein receptor-related protein 4 (Lrp4) is a critical protein involved in the Agrin-Lrp4-MuSK signaling pathway that drives the clustering of acetylcholine receptors (AChRs) at the neuromuscular junction (NMJ). Many studies have shown that Lrp4 also functions in kidney development, bone formation, nervous system development, etc. However, whether Lrp4 participates in nerve regeneration in mammals remains unknown. Herein, we show that Lrp4 is expressed in SCs and that conditional knockout (cKO) of Lrp4 in SCs promotes peripheral nerve regeneration. In Lrp4 cKO mice, the demyelination of SCs was accelerated, and the proliferation of SCs was increased in the injured nerve. Furthermore, we identified that two myelination-related genes, Krox-20 and Mpz, were downregulated more dramatically in the cKO group than in the control group. Our results elucidate a novel role of Lrp4 in peripheral nerve regeneration and thereby provide a potential therapeutic target for peripheral nerve recovery. [ABSTRACT FROM AUTHOR]

Abstract Background Myasthenia gravis is B-cell mediated autoimmune disease and is associated with antibodies against the acetylcholine receptor (AChR), muscle-specific kinase (MuSK) and lipoprotein-related protein 4 (LRP4) in the postsynaptic membrane at the neuromuscular junction. There are few studies on the concurrent presence of two positive antibodies in the sera of patients with myasthenia gravis. Case description A 32-year male admitted to the hospital with progressive neuromuscular weakness. He was diagnosed with Myasthenia gravis disorder mimicking Amyotrophic Lateral Sclerosis. We herein report a rare co-existence of three antibodies (anti-AChR, MuSK, and LRP4 antibodies) in the patient's serum. Conclusion We present a detailed clinical and laboratory analysis of the patient. This case report will emphasize the importance of evaluating anti-MuSK and anti-LRP4 antibodies even in patients with anti-AChR antibodies. [ABSTRACT FROM AUTHOR]