Disease relevance of AGRN

• These studies indicate that agrin is capable of accelerating the formation of insoluble protein fibrils in a second common neurodegenerative disease [1].
• Extracellular matrix and the blood-brain barrier in glioblastoma multiforme: spatial segregation of tenascin and agrin [2].
• To provide evidence on this point, we used anti-agrin IgG to disrupt agrin function in chick ciliary ganglion (CG) neuron/myotube cocultures [3].
• Myasthenia gravis can be induced in mice by injecting the extracellular domain of rat muscle-specific kinase (MuSK), a transmembrane receptor tyrosine kinase involved in agrin signaling at the neuromuscular junction [4].
• Agrin appears differentially expressed at the apical epithelial surface and acts as an HIV-1 attachment receptor [5].

Psychiatry related information on AGRN

• Particularly, it has been shown that agrin is associated with the pathological lesions of Alzheimer's disease (AD) and may contribute to the formation of beta-amyloid (Abeta) plaques in AD [1].

High impact information on AGRN

• Agrin, through its interaction with the receptor tyrosine kinase MuSK, mediates accumulation of acetylcholine receptors (AChR) at the developing neuromuscular junction [6].
• Colocalization with agrin binding sites at synapses supports the hypothesis that the alpha3NKA is a neuronal agrin receptor [6].
• An agrin fragment that acts as a competitive antagonist depresses action potential frequency, showing that endogenous agrin regulates native alpha3NKA function [6].
• The LNS domains of neurexin and agrin undergo alternative splicing that modulates their affinity for protein ligands in a neuron-specific manner [7].
• Here we characterize an agrin-binding site on the surface of muscle cells, show that this site corresponds to alpha-dystroglycan, and present evidence that alpha-dystroglycan is functionally related to agrin activity [8].

Chemical compound and disease context of AGRN

• Agrin is a major heparan sulfate proteoglycan accumulating in Alzheimer's disease brain [9].
• HIV-1-infected blood mononuclear cells form an integrin- and agrin-dependent viral synapse to induce efficient HIV-1 transcytosis across epithelial cell monolayer [5].

Biological context of AGRN

• Comparison of levels of agrin mRNA in fetal and adult human tissues showed a remarkable upregulation in adult kidney and lung [10].
• Agrin is a heparan sulfate proteoglycan involved in the development of the neuromuscular junction during embryogenesis [10].
• Furthermore, despite a high variability of vascular phenotypes, the loss of agrin strongly correlated with the expression of tenascin, an extracellular matrix molecule which has been described previously to be absent in mature non-pathological brain tissue and to accumulate in the basal lamina of tumor vessels [2].
• The activation loop tyrosines and the single juxtamembrane tyrosine were found to be essential for agrin-stimulated phosphorylation and clustering of AChRs [11].
• We found that N-linked glycosylation restrains ligand-independent tyrosine phosphorylation of MuSK and downstream signaling but is not necessary for agrin to stimulate MuSK [12].

Anatomical context of AGRN

• Agrin is a key organizer for postsynaptic differentiation at the neuromuscular junction (NMJ) [13].
• This activity requires the binding of agrin to the synaptic basal lamina via its N-terminal (NtA) domain [13].
• The association of agrin with PD lesions was also explored in PD human brain, and these studies shown that agrin colocalizes with alpha-synuclein in neuronal Lewy bodies in the substantia nigra of PD brain [1].
• The high transcription levels in lung and kidney corresponded with the accumulation of agrin in the alveolar and glomerular basement membranes, suggesting a filtration-associated function [10].
• In the central nervous system, agrin is widely expressed and concentrated at interneuronal synapses, but its function during synaptogenesis remains controversial [14].

Associations of AGRN with chemical compounds

• Agrin, a heparan sulfate proteoglycan, is a component of the basal lamina of BBB microvessels, and growing evidence suggests that it may be important for the maintenance of the BBB [2].
• The release of Agrin by motoneurons activates the muscle-specific receptor tyrosine kinase (MuSK) as the main organizer of subsynaptic specializations at the neuromuscular junction [15].
• In cultured myotubes, agrin stimulates the rapid phosphorylation of MuSK, leading to MuSK activation and tyrosine phosphorylation and clustering of acetylcholine receptors [12].
• Neural agrin activated MuSK in vitro if the lactosamine-containing mucin domain was present, and this activation was blocked in large part by Galbeta1,3GalNAc and Galbeta1,4GIcNAc [16].
• Heparin binding growth factors, proteases, adhesion molecules, and agrin all may be involved in the induction of AChR redistribution to form postsynaptic-like aggregates [17].

Physical interactions of AGRN

• Agrin binds alpha-synuclein and modulates alpha-synuclein fibrillation [1].
• Agrin protein binds the amyloidogenic peptide Abeta (1-40) in its fibrillar state via a mechanism that involves the heparan sulfate glycosaminoglycan chains of agrin [18].
• Agrin binds to a second protein complex on the muscle surface known as the dystrophin-associated glycoprotein complex [19].

Co-localisations of AGRN

• In the in vivo retina, more than 80% of the gephyrin clusters colocalized with extracellular agrin [20].

Regulatory relationships of AGRN

• Agrin activates MuSK and stimulates phosphorylation and clustering of acetylcholine receptors (AChRs) at synaptic sites [11].

Other interactions of AGRN

• We also show that agrin accelerates the formation of protofibrils by alpha-synuclein and decreases the half-time of fibril formation [1].
• Antibodies against agrin and against an unidentified GBM HSPG produced a strong staining of the GBM and the NMJ, different from that observed with anti-perlecan antibodies [21].
• We then review the development of the NMJ, focusing on the important roles of nerve-derived agrin and MuSK in clustering of AChRs and other essential components of the NMJ [22].
• Restriction of axon growth to the developing NMJ and formation of active zones for ACh release in the presynaptic terminal may be induced by molecules in the synaptic basal lamina, such as S-laminin, heparin binding growth factors, and agrin [17].
• Matrix metalloproteinase-3 removes agrin from synaptic basal lamina [23].

Analytical, diagnostic and therapeutic context of AGRN

• Quantitative ELISA showed that, compared with perlecan, the agrin-like GBM HSPG showed a sixfold higher molarity in crude glomerular extract [21].
• These results show that agrin is a major component of the GBM, indicating that it may play a role in renal ultrafiltration and cell matrix interaction [21].
• In immunoelectron microscopy, agrin showed a linear distribution along the GBM and was present throughout the width of the GBM [21].
• By using site-directed mutagenesis, we characterized the amino acids important for these activities of agrin [24].
• Agrin binding is saturable as measured by radioimmunoassay and, like agrin-induced AChR clustering, requires extracellular calcium [25].

References