View source for LINGO1

{{Infobox_gene}}
'''Leucine rich repeat and Immunoglobin-like domain-containing protein 1'''<ref>{{cite web | title = LINGO1 - Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 - LINGO1 gene & protein | url = https://www.uniprot.org/uniprot/Q96FE5 | work = UniProt | accessdate = 2015-10-17}}</ref> also known as '''LINGO-1''' is a [[protein]] which is encoded by the ''LINGO1'' [[gene]] in humans.<ref name="entrez">{{cite web | title = LINGO1 leucine rich repeat and Ig domain containing 1 | work = Entrez Gene |  url =https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=84894 }}</ref><ref name="pmid14686891">{{cite journal | vauthors = Carim-Todd L, Escarceller M, Estivill X, Sumoy L | title = LRRN6A/LERN1 (leucine-rich repeat neuronal protein 1) a novel gene with enriched expression in limbic system and neocortex | journal = The European Journal of Neuroscience | volume = 18 | issue = 12 | pages = 3167–82 | date = Dec 2003 | pmid = 14686891 | doi = 10.1111/j.1460-9568.2003.03003.x }}</ref> It belongs to the family of [[leucine-rich repeat]] proteins which are known for playing key roles<ref>{{cite journal | vauthors = de Wit J, Hong W, Luo L, Ghosh A | title = Role of leucine-rich repeat proteins in the development and function of neural circuits | journal = Annual Review of Cell and Developmental Biology | volume = 27 | pages = 697–729 | date = Jul 2011 | pmid =  | doi = 10.1146/annurev-cellbio-092910-154111 | url = http://www.its.caltech.edu/~whong/PDF/2011_de_Wit_&_Hong_Annu_Rev_Cell_Dev_Biol_27.pdf }}</ref> in the biology of the [[central nervous system]]. LINGO-1 is a functional component of the Nogo (neurite outgrowth inhibitor) receptor also known as the [[reticulon 4 receptor]]. 

It has been found that LINGO-1 antagonists such as [[BIIB033]]<ref>{{Cite web|title = BIIB033 {{!}} Multiple Sclerosis Discovery Forum|url = http://www.msdiscovery.org/research-resources/drug-pipeline/230-biib033|website = www.msdiscovery.org|accessdate = 2015-10-18}}</ref> could significantly improve and regulate survival after neural injury caused by the protein.<ref name="pmid25862159">{{cite journal | vauthors = Agúndez JA, Jiménez-Jimenez FJ, Alonso-Navarro H, García-Martín E | title = The potential of LINGO-1 as a therapeutic target for essential tremor | journal = Expert Opin. Ther. Targets | volume = 19 | issue = 8 | pages = 1139–48 | year = 2015 | pmid = 25862159 | doi = 10.1517/14728222.2015.1028360 }}</ref>

== Structure ==

[[File:Capture d’écran 2015-10-18 à 11.22.00.png|left|thumb|Aminoacidic sequence of the human LINGO-1 protein. The different domains are signaled according to their chemical characteristics and their aminoacids are identified.]]
The human LINGO-1 is a single-pass type 1 [[transmembrane protein]] of 614 amino acids. It contains a signal sequence of 34 residues, followed by a LRR ([[leucine-rich repeat]]) domain, an Ig (immunoglobulin-like) domain, a stalk domain, a transmembrane region and a short cytoplasmic tail. As a transmembrane protein, it can mostly be found on the [[cell membrane]].<ref>{{cite journal | vauthors = Mosyak L, Wood A, Dwyer B, Buddha M, Johnson M, Aulabaugh A, Zhong X, Presman E, Benard S, Kelleher K, Wilhelm J, Stahl ML, Kriz R, Gao Y, Cao Z, Ling HP, Pangalos MN, Walsh FS, Somers WS | title = The structure of the Lingo-1 ectodomain, a module implicated in central nervous system repair inhibition | journal = The Journal of Biological Chemistry | volume = 281 | issue = 47 | pages = 36378–90 | date = Nov 2006 | pmid = 17005555 | doi = 10.1074/jbc.M607314200 }}</ref>

The LINGO-1 structure has been shown to be highly stable both in its crystal form and in solution, thanks to its leucine-rich repeat Ig-composite fold. Since the tetramer has a very large surface area into the cell membrane, it is thought that this may serve as an efficient and stable binding platform, facilitating the interaction with NgR, p75, TROY complex.{{cn|date=November 2018}}
{{clear|left}}

=== Extracellular domain ===

The extracellular domain consists of the signal sequence, 11 LRR motifs comprised between an [[N-terminal]] and  [[C-terminal]] capping domains, and the Immunoglobulin-like ([[IgC2]]) domain.<ref name="pmid14686891" /><ref name="pmid14966521" /> The C-terminal LRR domain is essential for the protein's function with its screening for proteins that interact with this domain. The structure, together with biophysical analysis of LINGO-1 properties have revealed that the protein's LRR-Ig composite fold of the protein can drive it to associate with itself in a circular ring-like form, creating a closed and stable [[Tetrameric protein|tetramer]] in solution and in crystal.

=== Intracellular domain ===

The intracellular part of the protein is formed by the transmembrane region and a cytoplasmic tail of 38 residues. It contains a canonical [[Epidermal growth factor receptor|Epidermal Growth Factor Receptor]] (EGFR)-like tyrosine phosphorylation site on the 591 residue that is critical for intracellular signals.<ref name="pmid18186492">{{cite journal | vauthors = Llorens F, Gil V, Iraola S, Carim-Todd L, Martí E, Estivill X, Soriano E, del Rio JA, Sumoy L | title = Developmental analysis of Lingo-1/Lern1 protein expression in the mouse brain: interaction of its intracellular domain with Myt1l | journal = Developmental Neurobiology | volume = 68 | issue = 4 | pages = 521–41 | year = 2008 | pmid = 18186492 | doi = 10.1002/dneu.20607 }}</ref>

=== Co-receptor ===

LINGO-1 is a [[co-receptor]] that interacts with the ligand-binding [[reticulon 4 receptor|Nogo-66 receptor]] (NogoR) in the Nogo receptor signaling complex.<ref name="pmid14966521" /> The Nogo receptor complex is formed when Nogo-66 binds to its receptor.<ref>{{cite journal | vauthors = Alhoshani A, [[Vithayathil]] R, Weiss GA, Cocco MJ | title = Model of the Nogo: Nogo Receptor Complex | journal = Biophysical Journal | date = Jan 2014 | volume = 106 | issue = 22, Supplement 1  | pages = 410a–411a | doi = 10.1016/j.bpj.2013.11.2311 }}</ref>

LINGO-1 is an homotetramer which forms a ternary complex with [[Reticulon 4 receptor|RTN4R]]/[[Low-affinity nerve growth factor receptor|NGFR]] and RTN4R/[[TNFRSF19]].

==== Post-translational modifications ====

LINGO-1 contains several [[N-linked glycosylation|N-glycosylation sites]] that could have a negative effect on its capacity to self-interact with cis or trans, with other partners, or gangliosides.<ref name="ReferenceA">{{cite journal | vauthors = Jepson S, Vought B, Gross CH, Gan L, Austen D, Frantz JD, Zwahlen J, Lowe D, Markland W, Krauss R | title = LINGO-1, a transmembrane signaling protein, inhibits oligodendrocyte differentiation and myelination through intercellular self-interactions | journal = The Journal of Biological Chemistry | volume = 287 | issue = 26 | pages = 22184–95 | date = Jun 2012 | pmid = 22514275 | pmc = 3381180 | doi = 10.1074/jbc.M112.366179 }}</ref> It also contains high-mannose glycans.

== Tissue distribution ==
[[File:LINGO-1 expression.png|thumb|Graphical summary of the expression of the LINGO-1 gene in humans.
Blue is for the actions of the protein in the nervous system whereas purple represents the secretory function of LINGO-1 in the pancreas.
]]
LINGO-1 is expressed almost exclusively in the [[central nervous system]] (CNS). It can be found in the brain and in [[neuron]]s and [[oligodendrocyte]]s. LINGO-1 mRNA is expressed in an almost exclusive manner in the central nervous system during both embryonic and postnatal stages. It is targeted to the plasma membrane of neurons, but it is possible that a smaller quantities of the protein may be found in other intracellular compartments.<ref>{{cite web | title = LINGO1 Gene | url = https://www.genecards.org/cgi-bin/carddisp.pl?gene=LINGO1#_localization | work = Gene Cards | accessdate = 2015-10-18}}</ref> Its highest expression is in specific adult human brain regions such as the [[cerebral cortex]], a region involved in sensory-motor function, cognition and working memory; the [[hippocampus]], responsible for long term memory and the encoding and retrieval of multi-sensory information; the [[amygdala]], implicated in the stress response; as well as the [[thalamus]], with a more constant and basal level of expression across the remainder of the brain.<ref name="Andrews_2015">{{cite journal | vauthors = Andrews JL, Fernandez-Enright F | title = A decade from discovery to therapy: Lingo-1, the dark horse in neurological and psychiatric disorders | journal = Neuroscience & Biobehavioral Reviews | volume = 56 | issue = | pages = 97–114 | year = 2015 | pmid = 26143511 | doi = 10.1016/j.neubiorev.2015.06.009 }}</ref>

== Function and mode of action ==

Since LINGO-1 is a leucine-rich repeat protein, which are known for their important role in protein-protein interactions in a wide variety of cellular processes and their implication in important functions like neuronal differentiation and growth or the regulation of axon guidance and regeneration processes, it is logical to deduce that its functions are linked with the nervous system.{{cn|date=November 2018}}

LINGO-1 is an essential negative regulator of [[myelination]]. It has been implicated in the inhibition of axon regeneration through a ternary complex formed with [[reticulon 4 receptor|NgR1]]/Nogo-66 (ligand-binding subunit) and [[p75]] (signal transducing subunit). NgR1 relies on its co-receptors for transmembrane signalling.The three major myelin-associated inhibitory factors are Nogo, oligodendrocyte myelin glycoprotein, and myelin-associated glycoprotein which all share this trimolecular receptor complex. The inhibitory action is achieved through [[RhoA]]-[[Guanosine triphosphate|GTP]] upregulation in response to the presence of [[myelin oligodendrocyte glycoprotein|MOG]], [[myelin-associated glycoprotein|MAG]] or Nogo-66 in the central nervous system.<ref name="pmid14966521">{{cite journal | vauthors = Mi S, Lee X, Shao Z, Thill G, Ji B, Relton J, Levesque M, Allaire N, Perrin S, Sands B, Crowell T, Cate RL, McCoy JM, Pepinsky RB | title = LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex | journal = Nature Neuroscience | volume = 7 | issue = 3 | pages = 221–8 | date = Mar 2004 | pmid = 14966521 | doi = 10.1038/nn1188 }}</ref>  LINGO-1 also inhibits [[oligodendrocyte]] precursor differentiation and [[myelination]], by a mechanism that also involves activation of RhoA, but which apparently does not require p75 or NgR1.

LINGO-1 is involved in the regulation of neural apoptosis by inhibiting [[WNK3]] kinase activity. It has been shown that blocking the extracellular domain of LINGO-1 disrupts the interaction between receptor kinases and LINGO-1 which directly attenuates inhibition of neuronal survival. However among the four WNK family members, only WNK3 has been shown to regulate and increase cell survival in a caspase-3-dependant pathway.<ref name="ReferenceA"/><ref>{{cite journal | vauthors = Veríssimo F, Silva E, Morris JD, Pepperkok R, Jordan P | title = Protein kinase WNK3 increases cell survival in a caspase-3-dependent pathway | journal = Oncogene | volume = 25 | issue = 30 | pages = 4172–82 | date = Jul 2006 | pmid = 16501604 | doi = 10.1038/sj.onc.1209449 }}</ref>

To be able to understand how these components regulate signalling processes an experiment has been set up "model of serum deprivation" (SD) to prompt neuronal [[apoptosis]].{{cn|date=November 2018}} Research shows that treatments either with a construct containing the [[Immunoglobulin superfamily|IgC2]] or [[Epidermal growth factor receptor|EGFR]] domains in the LINGO1 protein or with Nogo66 which act like a NgR1 agonist, therefore initiating a physiological response when combined with the receptor, resulting in an increased rate of apoptosis in primary cultured cortical neurons under SD.{{cn|date=November 2018}}

In addition, reducing the expression levels of the serine/threonine Kinase WNK3 (using [[gene silencing]] via RNA interference ([[Small hairpin RNA|ShRNA]])) or inhibiting its kinase activity had similar effects on the survival of such neurons. The adverse effects of Nogo66<ref>{{cite journal | vauthors = Lee H, Raiker SJ, Venkatesh K, Geary R, Robak LA, Zhang Y, Yeh HH, Shrager P, Giger RJ | title = Synaptic function for the Nogo-66 receptor NgR1: regulation of dendritic spine morphology and activity-dependent synaptic strength | journal = The Journal of Neuroscience | volume = 28 | issue = 11 | pages = 2753–65 | date = Mar 2008 | pmid = 18337405 | doi = 10.1523/JNEUROSCI.5586-07.2008 }}</ref> have proved to enhance the co-association of LINGO1 and WNK3, causing the binding of WNK3 to the intracellular domain of LINGO1 leading to reduced WNK3 kinase activity. LINGO1 promotes neural apoptosis by inhibiting WNK3 kinase activity.<ref name="Zhang_2013">{{cite journal | vauthors = Zhang Z, Xu X, Xiang Z, Yu Z, Feng J, He C | title = LINGO-1 receptor promotes neuronal apoptosis by inhibiting WNK3 kinase activity | journal = The Journal of Biological Chemistry | volume = 288 | issue = 17 | pages = 12152–60 | date = Apr 2013 | pmid = 23482566 | pmc = 3636899 | doi = 10.1074/jbc.M112.447771 }}</ref>

== Signaling pathways ==

LINGO-1 is able to interact with different co-factors and co-receptors, which can lead to the activation o signaling pathways that can have an effect on the regulation of neuronal survival, axon regeneration, oligodendrocyte differentiation, or myelination processes in the brain.<ref>{{Cite web|title = Lingo1 protein (Mus musculus) - STRING network view|url = http://string-db.org/newstring_cgi/show_network_section.pl?taskId=GdocGH_yIOKn&interactive=no&network_flavor=actions|website = string-db.org|accessdate = 2015-10-30}}</ref>

Known interactions are with proteins such as Oligodendrocyte-myelinn glycoprotein, Nogo-A (neurotic outgrowth inhibitor), and myelin associated glycoproteins. LINGO-1 also interacts with transmembrane proteins: [[Epidermal growth factor receptor|EFGR]], along with its ligand [[epidermal growth factor]] (EFG); [[Brain-derived neurotrophic factor|brain derived neurotrophic factor]] (BNDF) and its receptor, [[amyloid precursor protein]] (APP), and tropomyosin receptor kinase A ([[Tropomyosin receptor kinase A|TrkA]]). There are other interactions with proteins that are implicated in neurological and psychiatric disorders: WNK lysine deficient protein in kinase 1 ([[WNK1]]), mitogen activated protein kinase 2/3 (MEK 2/3), extracellular signal reduced kinase 5 ([[ERK5]])[[RHOA|, RhoA]], and others.<ref name="pmid26143511" />

== Neurological and psychiatric disorders ==

[[File:LINGO-1 and pathological implications.png|thumb|333x333px|Representation of LINGO-1 signaling pathways that are implicated in neurological and psychiatric disorders. Interactions with the principal proteins mentioned and their pathological consequences.]]
LINGO-1 is coded by the LINGO-1 gene, which is located on the human [[Chromosome 15 (human)|chromosome 15]], more precisely on the locus 15q24-26, which is a region that has a primordial implication in number of psychiatric, addictive and anxiety related disorders. Genomic alterations of this regions can be factors for disorders such as schizophrenia, depression, autism, panic disorder or anxiety.<ref>{{Cite web|title = Chromosome 15|url = http://ghr.nlm.nih.gov/chromosome/15|website = Genetics Home Reference|date = 2015-10-26|accessdate = 2015-10-30}}</ref>

Brain regions identified as highly expressing Lingo-1 transcripts have also been heavily implicated in both neurological and psychiatric disorders such as [[spinal cord injury]], [[traumatic brain injury]], [[multiple sclerosis]] (MS), [[Parkinson's disease|Parkinson’s disease]], [[essential tremor]] (ET), [[Alzheimer's disease|Alzheimer’s disease]], [[epilepsy]] and [[glaucoma]] (central nervous system diseases); as well as stress and panic disorders, [[schizophrenia]], [[amnesia]], etc.<ref name="Andrews_2015" /> The role of Lingo-1 in these neurological disorders consists on its inhibitory role in neurite outgrowth, oligodendrocyte differentiation and myelination, making it difficult for the nervous system to regenerate the injured areas, whether these injuries come from endogenous or exogenous processes.

=== Spinal cord injury ===

[[Spinal cord injury]] results in the damage of the axonal tracts whose function is to control motor and sensory activity. This protein has been found in this axonal tracts of adolescent rat spinal cords following injury. Furthermore, a five time increase in Lingo-1 mRNA levels was detected 14 days post injury. Lingo-1-Fc, a soluble form of Lingo-1, has also been shown to antagonize Lingo-1 signaling pathways by inhibiting the binding of Lingo-1 to NgR, in consequence, vast improvements in the functional recovery of rats following lateral hemisection of the spinal cord were observed.<ref name="Andrews_2015" />

=== Essential tremor and Parkinson ===

[[Essential tremor]], one of the most common neurological diseases, is characterized by postural and action tremor. Recent research shows that around the 20% of people who suffer this disease have an increase of the protein LINGO1 in their [[cerebellum]], therefore linking LINGO1 to essential tremor would result in the development of more effective symptomatic therapies and treatment.<ref>{{cite journal | vauthors = Delay C, Tremblay C, Brochu E, Paris-Robidas S, Emond V, Rajput AH, Rajput A, Calon F | title = Increased LINGO1 in the cerebellum of essential tremor patients | journal = Movement Disorders | volume = 29 | issue = 13 | pages = 1637–47 | date = Nov 2014 | pmid = 24531928 | doi = 10.1002/mds.25819 }}</ref><ref>{{cite journal | vauthors = Kuo SH, Tang G, Louis ED, Ma K, Babji R, Balatbat M, Cortes E, Vonsattel JP, Yamamoto A, Sulzer D, Faust PL | title = Lingo-1 expression is increased in essential tremor cerebellum and is present in the basket cell pinceau | journal = Acta Neuropathologica | volume = 125 | issue = 6 | pages = 879–89 | date = Jun 2013 | pmid = 23543187 | doi = 10.1007/s00401-013-1108-7 | pmc=3663903}}</ref><ref name="pmid20372187">{{cite journal | vauthors = Tan EK | title = LINGO1 and essential tremor: linking the shakes. Linking LINGO1 to essential tremor | journal = Eur. J. Hum. Genet. | volume = 18 | issue = 7 | pages = 739–40 | year = 2010 | pmid = 20372187 | pmc = 2987372 | doi = 10.1038/ejhg.2010.25 }}</ref>

It has been found that there is a marker in LINGO-1 genome, a variant (rs9652490) that is significantly associated with essential tremor, increasing the risk of having the pathology.

As for Parkinson's disease, which is also an age-related movement disorder, it was discovers that levels of LINGO-1 are more elevated in the substantia nigra of post-mortem Parkinson's disease brains compared to control groups. It is thought that dopamine neuron survival and behavioral abnormalities are due to the over expression of LINGO-1 in Parkinson's patients.<ref name="Andrews_2015" />

=== Traumatic brain injury ===

[[Traumatic brain injury]] involves the necrotic and apoptotic death of brain cells in vulnerable and delicate areas such as the cerebral cortex and hippocampus, where it is known that there is an expression of Lingo-1 in both development and the adult stage of life. [[RhoA]] signaling is largely responsible for the neuronal response to neuronal inhibitory proteins and the regeneration (or lack of in case of its activation) of damaged axons. Receptor Lingo-1 stimulates RhoA, which activates [[Rho kinase|ROCK]] (RhoA kinase) which, in turn, stimulates [[LIM kinase]], which then stimulates [[cofilin]], which effectively reorganizes the [[actin]] cytoskeleton of the cell. In the case of neurons, activation of this pathway results in [[growth cone]] collapse, therefore inhibits the growth and repair of neural pathways and axons. Inhibition of this pathway by its various components usually results in some level of improved re-myelination.<ref>{{cite journal | vauthors = Yiu G, He Z | title = Glial inhibition of CNS axon regeneration | journal = Nature Reviews. Neuroscience | volume = 7 | issue = 8 | pages = 617–27 | date = Aug 2006 | pmid = 16858390 | pmc = 2693386 | doi = 10.1038/nrn1956 | url = http://www.nature.com/nrn/journal/v7/n8/full/nrn1956.html }}</ref> The use of Lingo-1-Fc as an antagonist for Lingo-1 shows the inhibition of RhoA activation. Since this soluble form of Lingo-1 is able to block the interactions between Lingo-1 and NgR, it is reasonable to think that the blockade of RhoA occurs at the level of Lingo-1/NgR/p75 or TROY complex, leading to the conclusion that Lingo-1plays a very important part in the lack of re-myelination, repair of neural and axon injuries, etc.<ref name="Andrews_2015" />

=== Schizophrenia ===

[[Schizophrenia]] is a chronic, severe and disabling brain [[Disorder (medicine)|disorder]].

As said before, leucine-rich repeat and immunoglobulin domain-containing protein (Lingo-1) is an essential negative regulator of [[myelination]] and neurite extension. Both myelination and [[Neurite outgrowth factor|neurite]] outgrowth occur during brain maturation, and it is during this late period of brain development (adolescence and early adulthood) when schizophrenia is first expressed. In fact, myelination peaks during late adolescence, coinciding with the onset of schizophrenia. Consequently, an excessive action of Lingo-1 through demyelination and blocking neurite extension may be one of the possible causes of this disorder.

The brain regions which are highly disrupted in the [[pathophysiology]] of this disease are [[hippocampus]] and [[dorsolateral prefrontal cortex]]. Therefore, clinical studies have been developed in order to study these brain regions in people who suffer schizophrenia. To investigate the hypothesis that myelin fraction is lower in schizophrenia patients than in healthy subjects, a technique called [[magnetic resonance spectroscopy]] (MRS), which allows analysis of myelin, is used. This studies reported that there was in fact, a dysfunctional profile of myelination in these two areas of the brain in schizophrenia sufferers.<ref>{{cite web | title = What Is Schizophrenia? | url = http://www.nimh.nih.gov/health/topics/schizophrenia/index.shtml | publisher = The National Institute of Mental Health (NIMH), U.S. Department of Health and Human Services | accessdate = 2015-10-28}}</ref>

[[Post-mortem examination|Post-mortem]] studies were then realized in order to compare the levels of the protein Lingo-1 in these two brain regions (hippocampus and dorsolateral prefrontal cortex) between schizophrenia and healthy subjects. Effectively, it was shown that the levels of Lingo-1 where significantly higher in schizophrenia than in control groups.<ref>{{cite journal | vauthors = Flynn SW, Lang DJ, Mackay AL, Goghari V, Vavasour IM, Whittall KP, Smith GN, Arango V, Mann JJ, Dwork AJ, Falkai P, Honer WG | title = Abnormalities of myelination in schizophrenia detected in vivo with MRI, and post-mortem with analysis of oligodendrocyte proteins | journal = Molecular Psychiatry | volume = 8 | issue = 9 | pages = 811–20 | date = Sep 2003 | pmid = 12931208 | doi = 10.1038/sj.mp.4001337 }}</ref>

Taking this into account, there is a clear relationship in between schizophrenia and demyelination, therefore, this disease is linked with Lingo-1 protein. Very possibly, an effective treatment of this disease would be the use of Lingo-1 antagonists, such as Anti-Lingo-1, which would offset the lack of myelin and hopefully avoid the disease. Thus, this treatment is still in ways of development and research.<ref>{{cite journal | vauthors = Fernandez-Enright F, Andrews JL, Newell KA, Pantelis C, Huang XF | title = Novel implications of Lingo-1 and its signaling partners in schizophrenia | journal = Translational Psychiatry | volume = 4 | issue = 1 | pages = e348 | date = 2014-01-21 | pmid = 24448210 | pmc = 3905231 | doi = 10.1038/tp.2013.121 }}</ref>

=== Multiple sclerosis ===

[[Multiple sclerosis]] is among the most common neurological disorders in young adults and it consists in the destructions and damage of the [[central nervous system]] (CNS) myelin due to persistent inflammation in the brain and spinal cord. This demyelination is shown to cause mitochondrial dysfunction in axons, leading to their degeneration. These damages disrupt the ability and capacity of the CNS to communicate, causing, therefore, a wide range of symptoms including physical, mental and even psychiatric ones. The best way of re-myelination is encouraging the differentiation of endogenous adult precursor cells into mature [[oligodendrocyte]]s in the injured regions. These precursor cells are called oligodendrocyte precursor cells (OPCs). It is known that in early stages of MS re-myelination can be achieved successfully and efficiently whereas it cannot in late and progressive stages. Regarding Lingo-1, we know that its signaling pathway is a negative regulator of OPCs differentiation, as well as Notch's and Wnt's.

Lingo-1 antagonists are able to promote re-myelination in CNS by means of stimulating OPCs differentiation which was before blocked by this protein. This has been seen in several experiments that resulted in significant increases of oligodendrocytes differentiation by targeting Lingo-1 with its antagonists, such as the antibody Anti-LINGO-1 ([[BIIB033]]).<ref name = "Huang_2011">{{cite journal | vauthors = Robson J, Trounson A | title = The potential of stem cells for 21st century neuroscience | journal = Neurochemistry International | volume = 59 | issue = 3 | pages = 327–8 | date = Sep 2011 | pmid = 21827925 | doi = 10.1016/J.NEUINT.2011.07.011 }}</ref>

=== Glaucoma ===

[[Glaucoma]] is a group neurodegenerative diseases characterized by features including morphological changes in the [[optic nerve]] head and therefore in the visual fields of the patients. There are two main types; open-angle and closed-angle glaucoma. The loss of RGCs ([[retinal ganglion cell]]s) and their axons  results in visual field loss.Increasing evidence also supports the existence of compartmentalized degeneration in synapses. It has been shown that the first symptoms of this disease are usually [[ocular hypertension]]. Elevated [[Intraocular pressure|IOP]] (intraocular pressure) has been identified as the etiology of glaucoma which causes neural RCG degeneration in the retina.<ref name="Fu_2015">{{cite book |title = Neural regeneration | editor-first1 = Kwok-Fai | editor-last1 = So | editor-first2 = Xiao-Ming | editor-last2 = Xu  | chapter = Chapter 17 – Neuroprotection of Retinal Ganglion Cells in Glaucoma by Blocking LINGO-1 Function or Using a Nogo-66 Receptor Antagonist  | last1 = Fu | first1 = Qing-Ling | last2 = So | first2 = Kwok-Fai | name-list-format = vanc | publisher = Elsevier Inc. | year = 2015 | isbn = 978-0-12-801732-6 | location = USA | pages = 263–271 | doi = 10.1016/B978-0-12-801732-6.00017-3 }}</ref>

LINGO1  was found to be expressed in the normal retina and was up regulated in RCGs after the induction of ocular hypertension in a rat chronic glaucoma model. Hence LINGO1 functions as a negative regulator of neuronal survival, axonal regeneration and oligodendrocyte differentiation. LINGO1 binds with [[Tropomyosin receptor kinase A|TrkA]] and inhibits myelination by oligodendrocytes in vitro. Further more it binds to [[Brain-derived neurotrophic factor|BDNF]] receptor and [[Tropomyosin receptor kinase B|TrkB]] inhibiting the activation of TkrB by binding of BNDF after the induction of ocular hypertension.

==== Neuroprotection of RCGs ====

Even though BDNF is an important survival factor for RGCs both during development and adult life,  BDNF can only slightly increase the survival rate of RCGs,<ref name="Fu_2015" /> and does not significantly “rescue” injured RCGs in hypertensive eyes after episcleral vein cauterization. The negative regulatory function of LINGO1 may be involved in the limited neuroprotective effect of BDNF and it could be reversed after blocking LINGO1 function.

LINGO 1 negatively regulates TrkB activation through the signalling pathway of BDNF/TrKB, and anti-LINGO-1 exerts neuroprotective effects via activation of BDNF/TrkB.<ref>{{cite journal | vauthors = Naylor RL, Robertson AG, Allen SJ, Sessions RB, Clarke AR, Mason GG, Burston JJ, Tyler SJ, Wilcock GK, Dawbarn D | title = A discrete domain of the human TrkB receptor defines the binding sites for BDNF and NT-4 | journal = Biochemical and Biophysical Research Communications | volume = 291 | issue = 3 | pages = 501–7 | date = Mar 2002 | pmid = 11855816 | doi = 10.1006/bbrc.2002.6468 }}</ref><ref>{{cite journal | vauthors = Haniu M, Montestruque S, Bures EJ, Talvenheimo J, Toso R, Lewis-Sandy S, Welcher AA, Rohde MF | title = Interactions between brain-derived neurotrophic factor and the TRKB receptor. Identification of two ligand binding domains in soluble TRKB by affinity separation and chemical cross-linking | journal = The Journal of Biological Chemistry | volume = 272 | issue = 40 | pages = 25296–303 | date = Oct 1997 | pmid = 9312147 | doi=10.1074/jbc.272.40.25296}}</ref>

Better than BDNF and BII003 (LINGO1 antagonist) alone, the combined treatment of both provides long term RCG neuroprotection after the induction of ocular hypertension. In conclusion BII033 may provide an attractive therapeutic strategy to promote neuroprotection in glaucoma.<ref name="Fu_2015" />

== Antagonists ==

Blocking the activity of lingo-1 has several potential applications in the treatment of [[neurodegenerative disease]]s.<ref name="pmid26143511">{{cite journal | vauthors = Andrews JL, Fernandez-Enright F | title = A decade from discovery to therapy: Lingo-1, the dark horse in neurological and psychiatric disorders | journal = Neurosci Biobehav Rev | volume = 56 | issue = | pages = 97–114 | year = 2015 | pmid = 26143511 | doi = 10.1016/j.neubiorev.2015.06.009 }}</ref><ref name="pmid23681979">{{cite journal | vauthors = Mi S, Pepinsky RB, Cadavid D | title = Blocking LINGO-1 as a therapy to promote CNS repair: from concept to the clinic | journal = CNS Drugs | volume = 27 | issue = 7 | pages = 493–503 | year = 2013 | pmid = 23681979 | doi = 10.1007/s40263-013-0068-8 }}</ref> 

(A [[myelin sheath]] is a lipid protective coating that covers and protects nerve cells (axons). These sheaths makes possible rapid and accurate transmission of nerve signals. [[Multiple sclerosis]] destroys these myelin sheaths, leading to a deterioration in nerve signal transmission. Once this protective myelin coating is stripped away, it leads to [[apoptosis]] of the neuron; axons gradually die, causing the muscle [[epileptic spasms|spasms]] and paralysis that are characteristic of the disease.<ref>{{cite web | first = Matthew | last = Herper | name-list-format = vanc | title = Biogen MS Drug Results Are 'Mildly Encouraging' In Eye Disease Test | url = https://www.forbes.com/sites/matthewherper/2015/04/14/biogen-ms-drug-results-are-mildly-encouraging-in-eye-disease-test/ | work = Forbes | date = 2015-10-25 | accessdate = 2015-10-29 }}</ref>)

=== Anti-lingo-1 (BIIB033) ===
Anti-lingo-1 ([[BIIB033]]) is a [[monoclonal antibody]] specific to the lingo-1 protein and is designed to promote [[remyelination]] (the formation of new myelin on [[axon]]s) and [[neuroprotection]].<ref name="Zhang_2013" /><ref name="pmid23448220">{{cite journal | vauthors = Deiß A, Brecht I, Haarmann A, Buttmann M | title = Treating multiple sclerosis with monoclonal antibodies: a 2013 update | journal = Expert Review of Neurotherapeutics | volume = 13 | issue = 3 | pages = 313–35 | year = 2013 | pmid = 23448220 | doi = 10.1586/ern.13.17 }}</ref>  The protein lingo-1 inhibits the action of myelin-making cells, [[oligodendrocyte]]s, which are surrounding the axons. Its antagonist, the antibody anti-lingo-1  would block this protein and even would be capable of myelin repair.

A number of clinical trials of the anti-lingo-1 antibody drug (BIIB033) have either been completed or are underway.<ref name="urlSearch of: BIIB033 - List Results - ClinicalTrials.gov">{{cite web | url = https://clinicaltrials.gov/ct2/results?term=BIIB033&Search=Search | title = BIIB033 Clinical Trials | work = ClinicalTrials.gov | accessdate = }}</ref> [[Optic neuritis|Acute optic neuritis]] (AON) is a disease which involves damage within the nerve fibers and loss of myelin within the optic nerve (it normally involves one eye and it's characterized by [[inflammation]]).<ref name="pmid19878630">{{cite journal | vauthors = Shams PN, Plant GT | title = Optic neuritis: a review | journal = International MS Journal / MS Forum | volume = 16 | issue = 3 | pages = 82–9 | date = Sep 2009 | pmid = 19878630 | url = http://www.msforum.net/Site/ViewPDF/ViewPDF.aspx?ArticleID=51D9410D-DCA3-43C4-8412-20FC039E5F5A&doctype=Article  }}</ref> One clinical trial studying the effects on BIIB033 on acute optic neuritis.<ref>{{ClinicalTrialsGov|NCT01721161|BIIB033 In Acute Optic Neuritis (AON) (RENEW)}}</ref> Throughout the study, optic nerve conduction latency was measured (the time for a signal to travel from the [[retina]] to the brain's [[visual cortex]]).<ref>{{cite web | title = Anti-LINGO-1 {{!}} Multiple Sclerosis Society UK | url = https://www.mssociety.org.uk/node/690821 | work = www.mssociety.org.uk | accessdate = 2015-10-29 | archive-url = https://web.archive.org/web/20151222113018/https://www.mssociety.org.uk/node/690821# | archive-date = 2015-12-22 | dead-url = yes | df =  }}</ref> As about half of [[patient]]s with optic neuritis will later develop multiple sclerosis, BIIB033 antibody treatment is also being considered for the former [[disease]]. It is thought that Anti-Lingo-1 would produce the necessary myelin to avoid [[neurodegeneration]].<ref>{{cite web | title = BIIB033 {{!}} Multiple Sclerosis Discovery Forum | url = http://www.msdiscovery.org/research-resources/drug-pipeline/230-biib033 | website = www.msdiscovery.org | accessdate = 2015-10-29}}</ref>

== References ==
{{reflist|33em}}

== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Saha N, Kolev M, Nikolov DB | title = Structural features of the Nogo receptor signaling complexes at the neuron/myelin interface | journal = Neuroscience Research | volume = 87 | issue = | pages = 1–7 | year = 2014 | pmid = 24956133 | doi = 10.1016/j.neures.2014.06.003 }}
* {{cite journal | vauthors = Carim-Todd L, Escarceller M, Estivill X, Sumoy L | title = LRRN6A/LERN1 (leucine-rich repeat neuronal protein 1), a novel gene with enriched expression in limbic system and neocortex | journal = The European Journal of Neuroscience | volume = 18 | issue = 12 | pages = 3167–82 | date = Dec 2003 | pmid = 14686891 | doi = 10.1111/j.1460-9568.2003.03003.x }}
* {{cite journal | vauthors = Mi S, Lee X, Shao Z, Thill G, Ji B, Relton J, Levesque M, Allaire N, Perrin S, Sands B, Crowell T, Cate RL, McCoy JM, Pepinsky RB | title = LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex | journal = Nature Neuroscience | volume = 7 | issue = 3 | pages = 221–8 | date = Mar 2004 | pmid = 14966521 | doi = 10.1038/nn1188 }}
* {{cite journal | vauthors = Shao Z, Browning JL, Lee X, Scott ML, Shulga-Morskaya S, Allaire N, Thill G, Levesque M, Sah D, McCoy JM, Murray B, Jung V, Pepinsky RB, Mi S | title = TAJ/TROY, an orphan TNF receptor family member, binds Nogo-66 receptor 1 and regulates axonal regeneration | journal = Neuron | volume = 45 | issue = 3 | pages = 353–9 | date = Feb 2005 | pmid = 15694322 | doi = 10.1016/j.neuron.2004.12.050 }}
* {{cite journal | vauthors = Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M | title = Towards a proteome-scale map of the human protein-protein interaction network | journal = Nature | volume = 437 | issue = 7062 | pages = 1173–8 | date = Oct 2005 | pmid = 16189514 | doi = 10.1038/nature04209 }}
* {{cite journal | vauthors = Mosyak L, Wood A, Dwyer B, Buddha M, Johnson M, Aulabaugh A, Zhong X, Presman E, Benard S, Kelleher K, Wilhelm J, Stahl ML, Kriz R, Gao Y, Cao Z, Ling HP, Pangalos MN, Walsh FS, Somers WS | title = The structure of the Lingo-1 ectodomain, a module implicated in central nervous system repair inhibition | journal = The Journal of Biological Chemistry | volume = 281 | issue = 47 | pages = 36378–90 | date = Nov 2006 | pmid = 17005555 | doi = 10.1074/jbc.M607314200 }}
* {{cite journal | vauthors = Satoh J, Tabunoki H, Yamamura T, Arima K, Konno H | title = TROY and LINGO-1 expression in astrocytes and macrophages/microglia in multiple sclerosis lesions | journal = Neuropathology and Applied Neurobiology | volume = 33 | issue = 1 | pages = 99–107 | date = Feb 2007 | pmid = 17239012 | doi = 10.1111/j.1365-2990.2006.00787.x }}
* {{cite journal | vauthors = Inoue H, Lin L, Lee X, Shao Z, Mendes S, Snodgrass-Belt P, Sweigard H, Engber T, Pepinsky B, Yang L, Beal MF, Mi S, Isacson O | title = Inhibition of the leucine-rich repeat protein LINGO-1 enhances survival, structure, and function of dopaminergic neurons in Parkinson's disease models | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 36 | pages = 14430–5 | date = Sep 2007 | pmid = 17726113 | pmc = 1955463 | doi = 10.1073/pnas.0700901104 }}
{{refend}}

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