LINGO1
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Leucine rich repeat and Immunoglobin-like domain-containing protein 1[5] also known as LINGO-1 is a protein which is encoded by the LINGO1 gene in humans.[6][7] It belongs to the family of leucine-rich repeat proteins which are known for playing key roles[8] 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 suggested that LINGO-1 antagonists such as BIIB033[9] could significantly improve and regulate survival after neural injury caused by the protein.[10]
Structure
The human LINGO-1 is a single-pass
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.[citation needed]
Extracellular domain
The extracellular domain consists of the signal sequence, 11 LRR motifs comprised between an
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 (EGFR)-like tyrosine phosphorylation site on the 591 residue that is critical for intracellular signals.[13]
Co-receptor
LINGO-1 is a co-receptor that interacts with the ligand-binding Nogo-66 receptor (NogoR) in the Nogo receptor signaling complex.[12] The Nogo receptor complex is formed when Nogo-66 binds to its receptor.[14]
LINGO-1 is an homotetramer which forms a ternary complex with RTN4R/NGFR and RTN4R/TNFRSF19.
Post-translational modifications
LINGO-1 contains several N-glycosylation sites that could have a negative effect on its capacity to self-interact with cis or trans, with other partners, or gangliosides.[15] It also contains high-mannose glycans.
Tissue distribution
LINGO-1 is expressed almost exclusively in the central nervous system (CNS). It can be found in the brain and in neurons and oligodendrocytes. 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.[16] 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.[17]
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.[citation needed]
LINGO-1 is an essential negative regulator of
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-dependent pathway.[15][18]
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.[citation needed] Research shows that treatments either with a construct containing the IgC2 or 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.[citation needed]
In addition, reducing the expression levels of the serine/threonine Kinase WNK3 (using
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.[21]
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:
Neurological and psychiatric disorders
LINGO-1 is coded by the LINGO-1 gene, which is located on the human
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, essential tremor (ET), Alzheimer's disease, epilepsy and glaucoma (central nervous system diseases); as well as stress and panic disorders, schizophrenia, amnesia, etc.[17] 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.[17]
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.[24][25][26]
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 and cerebellum[27] of post-mortem Parkinson's disease brains compared to control groups. Dudem et al., (2020)[27] also demonstrated that LINGO1 is a novel regulatory subunit of large conductance, Ca2+ activated (BK) channels. It is thought that dopamine neuron survival and behavioral abnormalities are due to the over expression of LINGO-1 in Parkinson's patients.[17]
Traumatic brain injury
Schizophrenia
As said before, leucine-rich repeat and immunoglobulin domain-containing protein (Lingo-1) is an essential negative regulator of
The brain regions which are highly disrupted in the
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.[31]
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 oligodendrocytes 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).[32]
Glaucoma
Glaucoma is a group of eye 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 cells) 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 IOP (intraocular pressure) has been identified as the etiology of glaucoma which causes neural RCG degeneration in the retina.[33]
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 TrkA and inhibits myelination by oligodendrocytes in vitro. Further more it binds to BDNF receptor and 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,[33] 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.[34][35]
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.[33]
Antagonists
Blocking the activity of lingo-1 has several potential applications in the treatment of neurodegenerative diseases.[22][36]
(A
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 axons) and neuroprotection.[20][38] The protein lingo-1 inhibits the action of myelin-making cells, oligodendrocytes, 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.
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000169783 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000049556 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "LINGO1 - Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 - LINGO1 gene & protein". UniProt. Retrieved 2015-10-17.
- ^ "LINGO1 leucine rich repeat and Ig domain containing 1". Entrez Gene.
- ^ S2CID 42086715.
- PMID 21740233. Archived from the original(PDF) on 2016-03-04. Retrieved 2015-10-17.
- ^ a b "BIIB033". Multiple Sclerosis Discovery Forum. Retrieved 2015-10-18.
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- ^ "Lingo1 protein (Mus musculus) - STRING network view". string-db.org. Retrieved 2015-10-30.
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- ^ "Chromosome 15". Genetics Home Reference. 2015-10-26. Retrieved 2015-10-30.
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- ^ "Schizophrenia". www.nimh.nih.gov. The National Institute of Mental Health (NIMH), U.S. Department of Health and Human Services. Retrieved 2015-10-28.
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- ^ Herper M (2015-10-25). "Biogen MS Drug Results Are 'Mildly Encouraging' In Eye Disease Test". Forbes. Retrieved 2015-10-29.
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- ^ "BIIB033 Clinical Trials". ClinicalTrials.gov.
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- ^ Clinical trial number NCT01721161 for "BIIB033 In Acute Optic Neuritis (AON) (RENEW)" at ClinicalTrials.gov
- ^ "Anti-LINGO-1". Multiple Sclerosis Society. Archived from the original on 2015-12-22. Retrieved 2015-10-29.
Further reading
- Saha N, Kolev M, Nikolov DB (2014). "Structural features of the Nogo receptor signaling complexes at the neuron/myelin interface". Neuroscience Research. 87: 1–7. S2CID 23707039.
- Carim-Todd L, Escarceller M, Estivill X, Sumoy L (Dec 2003). "LRRN6A/LERN1 (leucine-rich repeat neuronal protein 1), a novel gene with enriched expression in limbic system and neocortex". The European Journal of Neuroscience. 18 (12): 3167–82. S2CID 42086715.
- 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 (Mar 2004). "LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex". Nature Neuroscience. 7 (3): 221–8. S2CID 2344794.
- 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 (Feb 2005). "TAJ/TROY, an orphan TNF receptor family member, binds Nogo-66 receptor 1 and regulates axonal regeneration". Neuron. 45 (3): 353–9. PMID 15694322.
- 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 (Oct 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. S2CID 4427026.
- 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 (Nov 2006). "The structure of the Lingo-1 ectodomain, a module implicated in central nervous system repair inhibition". The Journal of Biological Chemistry. 281 (47): 36378–90. PMID 17005555.
- Satoh J, Tabunoki H, Yamamura T, Arima K, Konno H (Feb 2007). "TROY and LINGO-1 expression in astrocytes and macrophages/microglia in multiple sclerosis lesions". Neuropathology and Applied Neurobiology. 33 (1): 99–107. S2CID 36762956.
- 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 (Sep 2007). "Inhibition of the leucine-rich repeat protein LINGO-1 enhances survival, structure, and function of dopaminergic neurons in Parkinson's disease models". Proceedings of the National Academy of Sciences of the United States of America. 104 (36): 14430–5. PMID 17726113.