Agrin

Last updated
AGRN
Agrincartoon2.png
Identifiers
Aliases AGRN , CMS8, CMSPPD, agrin
External IDs OMIM: 103320 MGI: 87961 HomoloGene: 27907 GeneCards: AGRN
Orthologs
SpeciesHumanMouse
Entrez

375790

11603

Ensembl

ENSG00000188157

ENSMUSG00000041936

UniProt

O00468

A2ASQ1

RefSeq (mRNA)

NM_001305275
NM_198576
NM_001364727

NM_021604
NM_001369026
NM_001369027

RefSeq (protein)

NP_001292204
NP_940978
NP_001351656

NP_067617
NP_001355955
NP_001355956

Location (UCSC) Chr 1: 1.02 – 1.06 Mb Chr 4: 156.25 – 156.28 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
Agrin NtA domain
Identifiers
SymbolNtA
Pfam PF03146
InterPro IPR004850
SCOP2 1jc7 / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

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. [5] [6] [7]

Contents

This protein has nine domains homologous to protease inhibitors. [8] 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. [9]

Agrin functions by activating the MuSK protein (for Muscle-Specific Kinase), [10] which is a receptor tyrosine kinase required for the formation and maintenance of the neuromuscular junction. [11] Agrin is required to activate MuSK [12] . Agrin is also required for neuromuscular junction formation [13] .

Discovery

Agrin was first identified by the U.J. McMahan laboratory, Stanford University. [14]

Mechanism of action

During development in humans, the growing end of motor neuron axons secrete a protein called agrin. [15] 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). [16] [17] 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. [18] 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. [19]

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. [20]

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. [21]

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 [22] [23] and it influences Aβ homeostasis. [24]

Research

Agrin is investigated in relation with osteoarthritis. [25] [26] In addition, by its ability to activate the Hippo signaling pathway, agrin is emerging as a key proteoglycan in the tumor microenvironment. [27]

Clinical significance

AGRN gene mutation leads to congenital myasthenic syndromes [28] [29] [30] and myasthenia gravis. [31] [32]

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. [33] [34]

Related Research Articles

<span class="mw-page-title-main">Neuromuscular junction</span> Junction between the axon of a motor neuron and a muscle fiber

A neuromuscular junction is a chemical synapse between a motor neuron and a muscle fiber.

<span class="mw-page-title-main">Nicotinic acetylcholine receptor</span> Acetylcholine receptors named for their selective binding of nicotine

Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral nervous system, muscle, and many other tissues of many organisms. At the neuromuscular junction they are the primary receptor in muscle for motor nerve-muscle communication that controls muscle contraction. In the peripheral nervous system: (1) they transmit outgoing signals from the presynaptic to the postsynaptic cells within the sympathetic and parasympathetic nervous system, and (2) they are the receptors found on skeletal muscle that receive acetylcholine released to signal for muscular contraction. In the immune system, nAChRs regulate inflammatory processes and signal through distinct intracellular pathways. In insects, the cholinergic system is limited to the central nervous system.

<span class="mw-page-title-main">End-plate potential</span>

End plate potentials (EPPs) are the voltages which cause depolarization of skeletal muscle fibers caused by neurotransmitters binding to the postsynaptic membrane in the neuromuscular junction. They are called "end plates" because the postsynaptic terminals of muscle fibers have a large, saucer-like appearance. When an action potential reaches the axon terminal of a motor neuron, vesicles carrying neurotransmitters are exocytosed and the contents are released into the neuromuscular junction. These neurotransmitters bind to receptors on the postsynaptic membrane and lead to its depolarization. In the absence of an action potential, acetylcholine vesicles spontaneously leak into the neuromuscular junction and cause very small depolarizations in the postsynaptic membrane. This small response (~0.4mV) is called a miniature end plate potential (MEPP) and is generated by one acetylcholine-containing vesicle. It represents the smallest possible depolarization which can be induced in a muscle.

Synaptogenesis is the formation of synapses between neurons in the nervous system. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development, known as exuberant synaptogenesis. Synaptogenesis is particularly important during an individual's critical period, during which there is a certain degree of synaptic pruning due to competition for neural growth factors by neurons and synapses. Processes that are not used, or inhibited during their critical period will fail to develop normally later on in life.

<span class="mw-page-title-main">MuSK protein</span> Mammalian protein found in Homo sapiens

MuSK is a receptor tyrosine kinase required for the formation and maintenance of the neuromuscular junction. It is activated by a nerve-derived proteoglycan called agrin, which is similarly also required for neuromuscular junction formation.

<span class="mw-page-title-main">Perlecan</span>

Perlecan (PLC) also known as basement membrane-specific heparan sulfate proteoglycan core protein (HSPG) or heparan sulfate proteoglycan 2 (HSPG2), is a protein that in humans is encoded by the HSPG2 gene. The HSPG2 gene codes for a 4,391 amino acid protein with a molecular weight of 468,829. It is one of the largest known proteins. The name perlecan comes from its appearance as a "string of pearls" in rotary shadowed images.

<span class="mw-page-title-main">Heparan sulfate</span> Macromolecule

Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins. It is in this form that HS binds to a variety of protein ligands, including Wnt, and regulates a wide range of biological activities, including developmental processes, angiogenesis, blood coagulation, abolishing detachment activity by GrB, and tumour metastasis. HS has also been shown to serve as cellular receptor for a number of viruses, including the respiratory syncytial virus. One study suggests that cellular heparan sulfate has a role in SARS-CoV-2 Infection, particularly when the virus attaches with ACE2.

George D. Yancopoulos is a Greek-American biomedical scientist who is the co-founder, president and chief scientific officer of Regeneron Pharmaceuticals.

Dok-7 is a non-catalytic cytoplasmic adaptor protein that is expressed specifically in muscle and is essential for the formation of neuromuscular synapses. Further, Dok-7 contains pleckstrin homology (PH) and phosphotyrosine-binding (PTB) domains that are critical for Dok-7 function. Finally, mutations in Dok-7 are commonly found in patients with limb-girdle congenital myasthenia.

<span class="mw-page-title-main">Dystroglycan</span> Protein

Dystroglycan is a protein that in humans is encoded by the DAG1 gene.

<span class="mw-page-title-main">CTGF</span> Protein-coding gene in the species Homo sapiens

CTGF, also known as CCN2 or connective tissue growth factor, is a matricellular protein of the CCN family of extracellular matrix-associated heparin-binding proteins. CTGF has important roles in many biological processes, including cell adhesion, migration, proliferation, angiogenesis, skeletal development, and tissue wound repair, and is critically involved in fibrotic disease and several forms of cancers.

<span class="mw-page-title-main">Syndecan 1</span> Protein which in humans is encoded by the SDC1 gene

Syndecan 1 is a protein which in humans is encoded by the SDC1 gene. The protein is a transmembrane heparan sulfate proteoglycan and is a member of the syndecan proteoglycan family. The syndecan-1 protein functions as an integral membrane protein and participates in cell proliferation, cell migration and cell-matrix interactions via its receptor for extracellular matrix proteins. Syndecan-1 is a sponge for growth factors and chemokines, with binding largely via heparan sulfate chains. The syndecans mediate cell binding, cell signaling, and cytoskeletal organization and syndecan receptors are required for internalization of the HIV-1 tat protein.

Congenital myasthenic syndrome (CMS) is an inherited neuromuscular disorder caused by defects of several types at the neuromuscular junction. The effects of the disease are similar to Lambert-Eaton Syndrome and myasthenia gravis, the difference being that CMS is not an autoimmune disorder. There are only 600 known family cases of this disorder and it is estimated that its overall frequency in the human population is 1 in 200,000.

<span class="mw-page-title-main">Syndecan-4</span> Protein-coding gene in the species Homo sapiens

Syndecan-4 is a protein that in humans is encoded by the SDC4 gene. Syndecan-4 is one of the four vertebrate syndecans and has a molecular weight of ~20 kDa. Syndecans are the best-characterized plasma membrane proteoglycans. Their intracellular domain of membrane-spanning core protein interacts with actin cytoskeleton and signaling molecules in the cell cortex. Syndecans are normally found on the cell surface of fibroblasts and epithelial cells. Syndecans interact with fibronectin on the cell surface, cytoskeletal and signaling proteins inside the cell to modulate the function of integrin in cell-matrix adhesion. Also, syndecans bind to FGFs and bring them to the FGF receptor on the same cell. As a co-receptor or regulator, mutated certain proteoglycans could cause severe developmental defects, like disordered distribution or inactivation of signaling molecules.

<span class="mw-page-title-main">RAPSN</span> Protein-coding gene in the species Homo sapiens

43 kDa receptor-associated protein of the synapse (rapsyn) is a protein that in humans is encoded by the RAPSN gene.

<span class="mw-page-title-main">Syndecan-3</span> Protein-coding gene in the species Homo sapiens

Syndecan-3 is a protein that in humans is encoded by the SDC3 gene.

<span class="mw-page-title-main">Glypican 1</span> Protein-coding gene in the species Homo sapiens

Glypican-1 (GPC1) is a protein that in humans is encoded by the GPC1 gene. GPC1 is encoded by human GPC1 gene located at 2q37.3. GPC1 contains 558 amino acids with three predicted heparan sulfate chains.

<span class="mw-page-title-main">CHRNB1</span> Protein-coding gene in the species Homo sapiens

Acetylcholine receptor subunit beta is a protein that in humans is encoded by the CHRNB1 gene.

Neuromuscular junction disease is a medical condition where the normal conduction through the neuromuscular junction fails to function correctly.

The transforming growth factor beta (TGFβ) receptors are a family of serine/threonine kinase receptors involved in TGF beta signaling pathway. These receptors bind growth factor and cytokine signaling proteins in the TGF-beta family such as TGFβs, bone morphogenetic proteins (BMPs), growth differentiation factors (GDFs), activin and inhibin, myostatin, anti-Müllerian hormone (AMH), and NODAL.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000188157 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000041936 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Rupp F, Payan DG, Magill-Solc C, Cowan DM, Scheller RH (May 1991). "Structure and expression of a rat agrin". Neuron. 6 (5): 811–823. doi:10.1016/0896-6273(91)90177-2. PMID   1851019. S2CID   44440186.
  6. ↑ Kröger S, Schröder JE (October 2002). "Agrin in the developing CNS: new roles for a synapse organizer". News in Physiological Sciences. 17 (5): 207–212. doi: 10.1152/nips.01390.2002 . PMID   12270958. S2CID   2988918.
  7. ↑ Groffen AJ, Buskens CA, van Kuppevelt TH, Veerkamp JH, Monnens LA, van den Heuvel LP (May 1998). "Primary structure and high expression of human agrin in basement membranes of adult lung and kidney". European Journal of Biochemistry. 254 (1): 123–128. doi:10.1046/j.1432-1327.1998.2540123.x. PMID   9652404.
  8. ↑ Tsen G, Halfter W, Kröger S, Cole GJ (February 1995). "Agrin is a heparan sulfate proteoglycan". The Journal of Biological Chemistry. 270 (7): 3392–3399. doi: 10.1074/jbc.270.7.3392 . PMID   7852425.
  9. ↑ Groffen AJ, Ruegg MA, Dijkman H, van de Velden TJ, Buskens CA, van den Born J, et al. (January 1998). "Agrin is a major heparan sulfate proteoglycan in the human glomerular basement membrane". The Journal of Histochemistry and Cytochemistry. 46 (1): 19–27. doi: 10.1177/002215549804600104 . PMID   9405491.
  10. ↑ 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 (Sep 1995). "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. doi: 10.1016/0896-6273(95)90146-9 . PMID   7546737.
  11. ↑ 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 (May 1996). "The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo". Cell. 85 (4): 501–512. doi: 10.1016/s0092-8674(00)81251-9 . PMID   8653786.
  12. ↑ 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 (May 1996). "Agrin acts via a MuSK receptor complex". Cell. 85 (4): 513–523. doi: 10.1016/s0092-8674(00)81252-0 . PMID   8653787.
  13. ↑ Gautam M, Noakes PG, Moscoso L, Rupp F, Scheller RH, Merlie JP, Sanes JR (May 1996). "Defective neuromuscular synaptogenesis in agrin-deficient mutant mice". Cell. 85 (4): 525–535. doi: 10.1016/s0092-8674(00)81253-2 . PMID   8653788.
  14. ↑ Magill C, Reist NE, Fallon JR, Nitkin RM, Wallace BG, McMahan UJ (1987). Agrin. Progress in Brain Research. Vol. 71. pp. 391–396. doi:10.1016/S0079-6123(08)61840-3. ISBN   978-0-444-80814-1. PMID   3035610.
  15. ↑ Sanes JR, Lichtman JW (November 2001). "Induction, assembly, maturation and maintenance of a postsynaptic apparatus". Nature Reviews. Neuroscience. 2 (11): 791–805. doi:10.1038/35097557. PMID   11715056. S2CID   52802445.
  16. ↑ Glass DJ, Bowen DC, Stitt TN, Radziejewski C, Bruno J, Ryan TE, et al. (May 1996). "Agrin acts via a MuSK receptor complex". Cell. 85 (4): 513–523. doi: 10.1016/S0092-8674(00)81252-0 . PMID   8653787. S2CID   14930468.
  17. ↑ Sanes JR, Apel ED, Gautam M, Glass D, Grady RM, Martin PT, et al. (May 1998). "Agrin receptors at the skeletal neuromuscular junction". Annals of the New York Academy of Sciences. 841 (1): 1–13. Bibcode:1998NYASA.841....1S. doi:10.1111/j.1749-6632.1998.tb10905.x. PMID   9668217. S2CID   20097480.
  18. ↑ Gautam M, Noakes PG, Moscoso L, Rupp F, Scheller RH, Merlie JP, Sanes JR (May 1996). "Defective neuromuscular synaptogenesis in agrin-deficient mutant mice". Cell. 85 (4): 525–535. doi: 10.1016/S0092-8674(00)81253-2 . PMID   8653788. S2CID   12517490.
  19. ↑ Cheusova T, Khan MA, Schubert SW, Gavin AC, Buchou T, Jacob G, et al. (July 2006). "Casein kinase 2-dependent serine phosphorylation of MuSK regulates acetylcholine receptor aggregation at the neuromuscular junction". Genes & Development. 20 (13): 1800–1816. doi:10.1101/gad.375206. PMC   1522076 . PMID   16818610.
  20. ↑ PDB: 1PZ7 ​; Stetefeld J, Alexandrescu AT, Maciejewski MW, Jenny M, Rathgeb-Szabo K, Schulthess T, et al. (March 2004). "Modulation of agrin function by alternative splicing and Ca2+ binding". Structure. 12 (3): 503–515. doi: 10.1016/j.str.2004.02.001 . PMID   15016366.
  21. ↑ McDonnell KM, Grow WA (2004). "Reduced glycosaminoglycan sulfation diminishes the agrin signal transduction pathway". Developmental Neuroscience. 26 (1): 1–10. doi:10.1159/000080706. PMID   15509893. S2CID   42558266.
  22. ↑ Donahue JE, Berzin TM, Rafii MS, Glass DJ, Yancopoulos GD, Fallon JR, Stopa EG (May 1999). "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. Bibcode:1999PNAS...96.6468D. doi: 10.1073/pnas.96.11.6468 . PMC   26905 . PMID   10339611.
  23. ↑ Wolburg H, Noell S, Wolburg-Buchholz K, Mack A, Fallier-Becker P (April 2009). "Agrin, aquaporin-4, and astrocyte polarity as an important feature of the blood-brain barrier". The Neuroscientist. 15 (2): 180–193. doi:10.1177/1073858408329509. PMID   19307424. S2CID   25922007.
  24. ↑ Rauch SM, Huen K, Miller MC, Chaudry H, Lau M, Sanes JR, et al. (December 2011). "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. doi:10.1097/NEN.0b013e31823b0b12. PMC   3223604 . PMID   22082664.
  25. ↑ Thorup A, Dell'Accio F, Eldridge SE (16 September 2020). "Regrowing knee cartilage: new animal studies show promise". The Conversation. Retrieved 2020-10-12.
  26. ↑ Eldridge SE, Barawi A, Wang H, Roelofs AJ, Kaneva M, Guan Z, et al. (September 2020). "Agrin induces long-term osteochondral regeneration by supporting repair morphogenesis". Science Translational Medicine. 12 (559): eaax9086. doi:10.1126/scitranslmed.aax9086. hdl: 2164/15360 . PMID   32878982. S2CID   221469142.
  27. ↑ Chakraborty S, Hong W (February 2018). "Linking Extracellular Matrix Agrin to the Hippo Pathway in Liver Cancer and Beyond". Cancers. 10 (2): 45. doi: 10.3390/cancers10020045 . PMC   5836077 . PMID   29415512.
  28. ↑ Gan S, Yang H, Xiao T, Pan Z, Wu L (October 2020). "AGRN Gene Mutation Leads to Congenital Myasthenia Syndromes: A Pediatric Case Report and Literature Review". Neuropediatrics. 51 (5): 364–367. doi:10.1055/s-0040-1708534. PMID   32221959. S2CID   214694892.
  29. ↑ Ohkawara B, Shen X, Selcen D, Nazim M, Bril V, Tarnopolsky MA, et al. (April 2020). "Congenital myasthenic syndrome-associated agrin variants affect clustering of acetylcholine receptors in a domain-specific manner". JCI Insight. 5 (7): 132023. doi:10.1172/jci.insight.132023. PMC   7205260 . PMID   32271162.
  30. ↑ Xi J, Yan C, Liu WW, Qiao K, Lin J, Tian X, et al. (December 2017). "Novel SEA and LG2 Agrin mutations causing congenital Myasthenic syndrome". Orphanet Journal of Rare Diseases. 12 (1): 182. doi:10.1186/s13023-017-0732-z. PMC   5735900 . PMID   29258548.
  31. ↑ Zhang B, Shen C, Bealmear B, Ragheb S, Xiong WC, Lewis RA, et al. (2014-03-14). "Autoantibodies to agrin in myasthenia gravis patients". PLOS ONE. 9 (3): e91816. Bibcode:2014PLoSO...991816Z. doi: 10.1371/journal.pone.0091816 . PMC   3954737 . PMID   24632822.
  32. ↑ Yan M, Xing GL, Xiong WC, Mei L (February 2018). "Agrin and LRP4 antibodies as new biomarkers of myasthenia gravis". Annals of the New York Academy of Sciences. 1413 (1): 126–135. Bibcode:2018NYASA1413..126Y. doi:10.1111/nyas.13573. PMID   29377176. S2CID   46757850.
  33. ↑ Wightman DP, Jansen IE, Savage JE, Shadrin AA, Bahrami S, Holland D, et al. (September 2021). "A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease". Nature Genetics. 53 (9): 1276–1282. doi:10.1038/s41588-021-00921-z. hdl: 1871.1/61f01aa9-6dc7-4213-be2a-d3fe622db488 . PMC   10243600 . PMID   34493870. S2CID   237442349.
  34. ↑ Rahman MM, Lendel C (August 2021). "Extracellular protein components of amyloid plaques and their roles in Alzheimer's disease pathology". Molecular Neurodegeneration. 16 (1): 59. doi:10.1186/s13024-021-00465-0. PMC   8400902 . PMID   34454574.

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.