protein
Agrin
Gene
AGRN
Organism
Homo sapiens(9606)
Length
2068 aa
Mass
217,320 Da
Agrin (AGRN) is a large heparan sulfate proteoglycan that functions as a critical organizer of neuromuscular and neuronal synapses. As a secreted or transmembrane protein, it nucleates acetylcholine receptor (AChR) clustering and postsynaptic differentiation through the AGRN-LRP4-MUSK signaling complex, and also modulates dendritic filopodia formation, calcium homeostasis, and neurite outgrowth in the central nervous system (UniProt: O00468). Alternative splicing of AGRN generates multiple isoforms with distinct activities; neuron-specific z+ isoforms are potent AChR activators, while the transmembrane form predominates in the brain and promotes synapse formation in hippocampal neurons.
Agrin is primarily expressed in neurons and at the neuromuscular junction, where it is essential for synaptic stability and plasticity. Mutations in AGRN cause congenital myasthenic syndrome type 8 (CMS8, MIM 615120), an autosomal recessive disorder of neuromuscular transmission (UniProt: O00468). The protein also participates in positive regulation of cartilage formation through alpha-dystroglycan signaling.
In Alzheimer's disease, agrin is significantly upregulated in post-mortem AD brain tissue relative to age-matched controls (mean log2 fold-change +0.82; Chaparral AD proteomics). This upregulation suggests a potential compensatory or pathological response to synaptic dysfunction in AD pathology, though the functional consequences remain to be clarified.
Generated from the curated entity record below. May contain errors — verify against source links.
Proteomics Evidence · AD
↑ Up in ADP3
not detected
P2
not detected
S2
+0.816
S3
not detected
Mean log₂FC across detected fractions: +0.8156 (1 of 4 fractions detected)
Human post-mortem AD brain vs age-matched controls, TMT-labeled, 4 subcellular fractions (P2, P3, S2, S3), DDA proteomics.
Related Publications
Browse all →Tau molecular diversity contributes to clinical heterogeneity in Alzheimer's disease.
Dujardin Simon et al.Nature medicine2020PMID 32572268Deep Multilayer Brain Proteomics Identifies Molecular Networks in Alzheimer's Disease Progression.
Bai Bing et al.Neuron2020PMID 31926610A Multi-network Approach Identifies Protein-Specific Co-expression in Asymptomatic and Symptomatic Alzheimer's Disease.
Seyfried Nicholas T et al.Cell systems2017PMID 27989508Large-scale deep multi-layer analysis of Alzheimer's disease brain reveals strong proteomic disease-related changes not observed at the RNA level.
Johnson Erik C B et al.Nature neuroscience2022PMID 35115731Organization and regulation of gene transcription.
Cramer PatrickNature2019PMID 31462772
Function
Depending on alternative splicing and post-translational modifications, it has a role in different processes, including neuromuscular junction formation and maintenance, and regulation of neurite outgrowth (By similarity). Also involved in positive regulation of cartilage formation through alpha-dystroglycan binding and up-regulation of SOX9 (PubMed:26290588)
Heparan sulfate basal lamina glycoprotein that plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ) and directs key events in postsynaptic differentiation. Component of the AGRN-LRP4 receptor complex that induces the phosphorylation and activation of MUSK (PubMed:21969364). The activation of MUSK in myotubes induces the formation of NMJ by regulating different processes including the transcription of specific genes and the clustering of AChR in the postsynaptic membrane. Calcium ions are required for maximal AChR clustering. AGRN function in neurons is highly regulated by alternative splicing, glycan binding and proteolytic processing. Modulates calcium ion homeostasis in neurons, specifically by inducing an increase in cytoplasmic calcium ions. Functions differentially in the central nervous system (CNS) by inhibiting the alpha(3)-subtype of Na+/K+-ATPase and evoking depolarization at CNS synapses. This secreted isoform forms a bridge, after release from motor neurons, to basal lamina through binding laminin via the NtA domain
Transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases
Isoform 1, isoform 4 and isoform 5: neuron-specific (z+) isoforms that contain C-terminal insertions of 8-19 AA are potent activators of AChR clustering. Isoform 5, agrin (z+8), containing the 8-AA insert, forms a receptor complex in myotubules containing the neuronal AGRN, the muscle-specific kinase MUSK and LRP4, a member of the LDL receptor family. The splicing factors, NOVA1 and NOVA2, regulate AGRN splicing and production of the 'z' isoforms
Muscle-specific isoform, probably involved in endothelial cell differentiation
Involved in the positive regulation of cartilage formation, acting through alpha-dystroglycan binding and up-regulation of SOX9, a transcription factor that plays a key role in chondrocytes differentiation
Is involved in regulation of neurite outgrowth probably due to the presence of the glycosaminoglcan (GAG) side chains of heparan and chondroitin sulfate attached to the Ser/Thr- and Gly/Ser-rich regions. Also involved in modulation of growth factor signaling (By similarity)
This released fragment is important for agrin signaling and to exert a maximal dendritic filopodia-inducing effect. All 'z' splice variants (z+) of this fragment also show an increase in the number of filopodia
Disease associations
Myasthenic syndrome, congenital, 8CMS8
A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness. CMS8 is an autosomal recessive disease characterized by prominent defects of both the pre- and postsynaptic regions. Affected individuals have onset of muscle weakness in early childhood; the severity of the weakness and muscles affected is variable.
Sources
Last updated 5/8/2026, 6:35:57 AM