Agrin Explained

Agrin is a large proteoglycan whose best-characterised role is in the development of the neuromuscular junction during embryogenesis. Agrin is named based on its involvement in the aggregation of acetylcholine receptors during synaptogenesis. In humans, this protein is encoded by the AGRN gene.[1] [2] [3]

This protein has nine domains homologous to protease inhibitors.[4] It may also have functions in other tissues and during other stages of development. It is a major proteoglycan component in the glomerular basement membrane and may play a role in the renal filtration and cell-matrix interactions.[5]

Agrin functions by activating the MuSK protein (for Muscle-Specific Kinase), [6] which is a receptor tyrosine kinase required for the formation and maintenance of the neuromuscular junction.[7] Agrin is required to activate MuSK.[8] Agrin is also required for neuromuscular junction formation.[9]

Discovery

Agrin was first identified by the U.J. McMahan laboratory, Stanford University.[10]

Mechanism of action

During development in humans, the growing end of motor neuron axons secrete a protein called agrin.[11] When secreted, agrin binds to several receptors on the surface of skeletal muscle. The receptor which appears to be required for the formation of the neuromuscular junction (NMJ) is called the MuSK receptor (Muscle specific kinase).[12] [13] MuSK is a receptor tyrosine kinase - meaning that it induces cellular signaling by causing the addition of phosphate molecules to particular tyrosines on itself and on proteins that bind the cytoplasmic domain of the receptor.

In addition to MuSK, agrin binds several other proteins on the surface of muscle, including dystroglycan and laminin. It is seen that these additional binding steps are required to stabilize the NMJ.

The requirement for Agrin and MuSK in the formation of the NMJ was demonstrated primarily by knockout mouse studies. In mice that are deficient for either protein, the neuromuscular junction does not form.[14] Many other proteins also comprise the NMJ, and are required to maintain its integrity. For example,MuSK also binds a protein called "dishevelled" (Dvl), which is in the Wnt signalling pathway. Dvl is additionally required for MuSK-mediated clustering of AChRs, since inhibition of Dvl blocks clustering.

Signaling

The nerve secretes agrin, resulting in phosphorylation of the MuSK receptor.

It seems that the MuSK receptor recruits casein kinase 2, which is required for clustering.[15]

A protein called rapsyn is then recruited to the primary MuSK scaffold, to induce the additional clustering of acetylcholine receptors (AChR). This is thought of as the secondary scaffold. A protein called Dok-7 has shown to be additionally required for the formation of the secondary scaffold; it is apparently recruited after MuSK phosphorylation and before acetylcholine receptors are clustered.

Structure

There are three potential heparan sulfate (HS) attachment sites within the primary structure of agrin, but it is thought that only two of these actually carry HS chains when the protein is expressed.

In fact, one study concluded that at least two attachment sites are necessary by inducing synthetic agents. Since agrin fragments induce acetylcholine receptor aggregation as well as phosphorylation of the MuSK receptor, researchers spliced them and found that the variant did not trigger phosphorylation. It has also been shown that the G3 domain of agrin is very plastic, meaning it can discriminate between binding partners for a better fit.[16]

Heparan sulfate glycosaminoglycans covalently linked to the agrin protein have been shown to play a role in the clustering of AChR. Interference in the correct formation of heparan sulfate through the addition of chlorate to skeletal muscle cell culture results in a decrease in the frequency of spontaneous acetylcholine receptor (AChR) clustering. It may be that rather than solely binding directly to the agrin protein core a number of components of the secondary scaffold may also interact with its heparan sulfate side-chains.[17]

A role in the retention of anionic macromolecules within the vasculature has also been suggested for agrin-linked HS at the glomerular or alveolar basement membrane.

Functions

Agrin may play an important role in the basement membrane of the microvasculature as well as in synaptic plasticity. Also, agrin may be involved in blood–brain barrier (BBB) formation and/or function [18] [19] and it influences Aβ homeostasis.[20]

Research

Agrin is investigated in relation with osteoarthritis.[21] [22] In addition, by its ability to activate the Hippo signaling pathway, agrin is emerging as a key proteoglycan in the tumor microenvironment.[23]

Clinical significance

AGRN gene mutation leads to congenital myasthenic syndromes[24] [25] [26] and myasthenia gravis.[27] [28]

A recent genome-wide association study (GWAS) has found that genetic variations in AGRN are associated with late-onset sporadic Alzheimer’s disease (LOAD). These genetic variations alter β-amyloid homeostasis contributing to its accumulation and plaque formation.[29] [30]

Further reading

Notes and References

  1. Rupp F, Payan DG, Magill-Solc C, Cowan DM, Scheller RH . Structure and expression of a rat agrin . Neuron . 6 . 5 . 811–823 . May 1991 . 1851019 . 10.1016/0896-6273(91)90177-2 . 44440186 .
  2. Kröger S, Schröder JE . Agrin in the developing CNS: new roles for a synapse organizer . News in Physiological Sciences . 17 . 5 . 207–212 . October 2002 . 12270958 . 10.1152/nips.01390.2002 . 2988918 . free .
  3. Groffen AJ, Buskens CA, van Kuppevelt TH, Veerkamp JH, Monnens LA, van den Heuvel LP . Primary structure and high expression of human agrin in basement membranes of adult lung and kidney . European Journal of Biochemistry . 254 . 1 . 123–128 . May 1998 . 9652404 . 10.1046/j.1432-1327.1998.2540123.x . free .
  4. Tsen G, Halfter W, Kröger S, Cole GJ . Agrin is a heparan sulfate proteoglycan . The Journal of Biological Chemistry . 270 . 7 . 3392–3399 . February 1995 . 7852425 . 10.1074/jbc.270.7.3392 . free .
  5. Groffen AJ, Ruegg MA, Dijkman H, van de Velden TJ, Buskens CA, van den Born J, Assmann KJ, Monnens LA, Veerkamp JH, van den Heuvel LP . 6 . Agrin is a major heparan sulfate proteoglycan in the human glomerular basement membrane . The Journal of Histochemistry and Cytochemistry . 46 . 1 . 19–27 . January 1998 . 9405491 . 10.1177/002215549804600104 . 24353753 .
  6. Valenzuela DM, Stitt TN, DiStefano PS, Rojas E, Mattsson K, Compton DL, Nunez L, Park JS, Stark JL, Gies DR, Thomas S, LeBeau MM, Fernald AA, Copeland NG, Jenkins NA, Burden SJ, Glass DJ, Yancopoulos GD . Receptor tyrosine kinase specific for the skeletal muscle lineage: expression in embryonic muscle, at the neuromuscular junction, and after injury . Neuron . 15 . 3 . 573–584 . Sep 1995 . 7546737 . 10.1016/0896-6273(95)90146-9 . free .
  7. DeChiara TM, Bowen DC, Valenzuela DM, Simmons MV, Poueymirou WT, Thomas S, Kinetz E, Compton DL, Rojas E, Park JS, Smith C, DiStefano PS, Glass DJ, Burden SJ, Yancopoulos GD . The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo . Cell . 85 . 4 . 501–512 . May 1996 . 8653786 . 10.1016/s0092-8674(00)81251-9 . free .
  8. Glass DJ, Bowen DC, Stitt TN, Radziejewski C, Bruno J, Ryan TE, Gies DR, Shah S, Mattson K, Burden SJ, DiStefano PS, Valenzuela DM, DeChiara TM, Yancopoulos GD . Agrin acts via a MuSK receptor complex . Cell . 85 . 4 . 513–523 . May 1996 . 8653787 . 10.1016/s0092-8674(00)81252-0 . free .
  9. Gautam M, Noakes PG, Moscoso L, Rupp F, Scheller RH, Merlie JP, Sanes JR . Defective neuromuscular synaptogenesis in agrin-deficient mutant mice . Cell . 85 . 4 . 525–535 . May 1996 . 8653788 . 10.1016/s0092-8674(00)81253-2 . free .
  10. Book: Magill C, Reist NE, Fallon JR, Nitkin RM, Wallace BG, McMahan UJ . Chapter 32 Agrin . Neural Regeneration . 71 . 391–396 . 1987 . 3035610 . 10.1016/S0079-6123(08)61840-3 . 978-0-444-80814-1 . Progress in Brain Research .
  11. Sanes JR, Lichtman JW . Induction, assembly, maturation and maintenance of a postsynaptic apparatus . Nature Reviews. Neuroscience . 2 . 11 . 791–805 . November 2001 . 11715056 . 10.1038/35097557 . 52802445 .
  12. Glass DJ, Bowen DC, Stitt TN, Radziejewski C, Bruno J, Ryan TE, Gies DR, Shah S, Mattsson K, Burden SJ, DiStefano PS, Valenzuela DM, DeChiara TM, Yancopoulos GD . 6 . Agrin acts via a MuSK receptor complex . Cell . 85 . 4 . 513–523 . May 1996 . 8653787 . 10.1016/S0092-8674(00)81252-0 . 14930468 . free .
  13. Sanes JR, Apel ED, Gautam M, Glass D, Grady RM, Martin PT, Nichol MC, Yancopoulos GD . 6 . Agrin receptors at the skeletal neuromuscular junction . Annals of the New York Academy of Sciences . 841 . 1 . 1–13 . May 1998 . 9668217 . 10.1111/j.1749-6632.1998.tb10905.x . 20097480 . 1998NYASA.841....1S .
  14. Gautam M, Noakes PG, Moscoso L, Rupp F, Scheller RH, Merlie JP, Sanes JR . Defective neuromuscular synaptogenesis in agrin-deficient mutant mice . Cell . 85 . 4 . 525–535 . May 1996 . 8653788 . 10.1016/S0092-8674(00)81253-2 . 12517490 . free .
  15. Cheusova T, Khan MA, Schubert SW, Gavin AC, Buchou T, Jacob G, Sticht H, Allende J, Boldyreff B, Brenner HR, Hashemolhosseini S . 6 . Casein kinase 2-dependent serine phosphorylation of MuSK regulates acetylcholine receptor aggregation at the neuromuscular junction . Genes & Development . 20 . 13 . 1800–1816 . July 2006 . 16818610 . 1522076 . 10.1101/gad.375206 .
  16. Stetefeld J, Alexandrescu AT, Maciejewski MW, Jenny M, Rathgeb-Szabo K, Schulthess T, Landwehr R, Frank S, Ruegg MA, Kammerer RA . 6 . Modulation of agrin function by alternative splicing and Ca2+ binding . Structure . 12 . 3 . 503–515 . March 2004 . 15016366 . 10.1016/j.str.2004.02.001 . free .
  17. McDonnell KM, Grow WA . Reduced glycosaminoglycan sulfation diminishes the agrin signal transduction pathway . Developmental Neuroscience . 26 . 1 . 1–10 . 2004 . 15509893 . 10.1159/000080706 . 42558266 .
  18. Donahue JE, Berzin TM, Rafii MS, Glass DJ, Yancopoulos GD, Fallon JR, Stopa EG . Agrin in Alzheimer's disease: altered solubility and abnormal distribution within microvasculature and brain parenchyma . Proceedings of the National Academy of Sciences of the United States of America . 96 . 11 . 6468–6472 . May 1999 . 10339611 . 26905 . 10.1073/pnas.96.11.6468 . 1999PNAS...96.6468D . free .
  19. Wolburg H, Noell S, Wolburg-Buchholz K, Mack A, Fallier-Becker P . Agrin, aquaporin-4, and astrocyte polarity as an important feature of the blood-brain barrier . The Neuroscientist . 15 . 2 . 180–193 . April 2009 . 19307424 . 10.1177/1073858408329509 . 25922007 .
  20. Rauch SM, Huen K, Miller MC, Chaudry H, Lau M, Sanes JR, Johanson CE, Stopa EG, Burgess RW . 6 . Changes in brain β-amyloid deposition and aquaporin 4 levels in response to altered agrin expression in mice . Journal of Neuropathology and Experimental Neurology . 70 . 12 . 1124–1137 . December 2011 . 22082664 . 3223604 . 10.1097/NEN.0b013e31823b0b12 .
  21. Web site: Thorup. Anne-Sophie. Dell'Accio. Francesco. Eldridge. Suzanne E. . vanc . Regrowing knee cartilage: new animal studies show promise. 2020-10-12. The Conversation. 16 September 2020 . en.
  22. Eldridge SE, Barawi A, Wang H, Roelofs AJ, Kaneva M, Guan Z, Lydon H, Thomas BL, Thorup AS, Fernandez BF, Caxaria S, Strachan D, Ali A, Shanmuganathan K, Pitzalis C, Whiteford JR, Henson F, McCaskie AW, De Bari C, Dell'Accio F . 6 . Agrin induces long-term osteochondral regeneration by supporting repair morphogenesis . Science Translational Medicine . 12 . 559 . eaax9086 . September 2020 . 32878982 . 10.1126/scitranslmed.aax9086 . free . 221469142 . 2164/15360 .
  23. Chakraborty S, Hong W . Linking Extracellular Matrix Agrin to the Hippo Pathway in Liver Cancer and Beyond . Cancers . 10 . 2 . 45 . February 2018 . 29415512 . 5836077 . 10.3390/cancers10020045 . free .
  24. Gan S, Yang H, Xiao T, Pan Z, Wu L . AGRN Gene Mutation Leads to Congenital Myasthenia Syndromes: A Pediatric Case Report and Literature Review . Neuropediatrics . 51 . 5 . 364–367 . October 2020 . 32221959 . 10.1055/s-0040-1708534 . 214694892 .
  25. Ohkawara B, Shen X, Selcen D, Nazim M, Bril V, Tarnopolsky MA, Brady L, Fukami S, Amato AA, Yis U, Ohno K, Engel AG . 6 . Congenital myasthenic syndrome-associated agrin variants affect clustering of acetylcholine receptors in a domain-specific manner . JCI Insight . 5 . 7 . 132023 . April 2020 . 32271162 . 7205260 . 10.1172/jci.insight.132023 .
  26. Xi J, Yan C, Liu WW, Qiao K, Lin J, Tian X, Wu H, Lu J, Wong LJ, Beeson D, Zhao C . 6 . Novel SEA and LG2 Agrin mutations causing congenital Myasthenic syndrome . Orphanet Journal of Rare Diseases . 12 . 1 . 182 . December 2017 . 29258548 . 5735900 . 10.1186/s13023-017-0732-z . free .
  27. Zhang B, Shen C, Bealmear B, Ragheb S, Xiong WC, Lewis RA, Lisak RP, Mei L . 6 . Autoantibodies to agrin in myasthenia gravis patients . PLOS ONE . 9 . 3 . e91816 . 2014-03-14 . 24632822 . 3954737 . 10.1371/journal.pone.0091816 . 2014PLoSO...991816Z . free .
  28. Yan M, Xing GL, Xiong WC, Mei L . Agrin and LRP4 antibodies as new biomarkers of myasthenia gravis . Annals of the New York Academy of Sciences . 1413 . 1 . 126–135 . February 2018 . 29377176 . 10.1111/nyas.13573 . 2018NYASA1413..126Y . 46757850 .
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  30. Rahman MM, Lendel C . Extracellular protein components of amyloid plaques and their roles in Alzheimer's disease pathology . Molecular Neurodegeneration . 16 . 1 . 59 . August 2021 . 34454574 . 8400902 . 10.1186/s13024-021-00465-0 . free .

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