Nat Neurosci. 2004 Mar;7(3):221-8. Epub 2004 Feb 15.
LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex.
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.
Department of Discovery Biology, Biogen Idec, Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, USA. email@example.com
Axon regeneration in the adult CNS is prevented by inhibitors in myelin. These inhibitors seem to modulate RhoA activity by binding to a receptor complex comprising a ligand-binding subunit (the Nogo-66 receptor NgR1) and a signal transducing subunit (the neurotrophin receptor p75). However, in reconstituted non-neuronal systems, NgR1 and p75 together are unable to activate RhoA, suggesting that additional components of the receptor may exist. Here we describe LINGO-1, a nervous system-specific transmembrane protein that binds NgR1 and p75 and that is an additional functional component of the NgR1/p75 signaling complex. In non-neuronal cells, coexpression of human NgR1, p75 and LINGO-1 conferred responsiveness to oligodendrocyte myelin glycoprotein, as measured by RhoA activation. A dominant-negative human LINGO-1 construct attenuated myelin inhibition in transfected primary neuronal cultures. This effect on neurons was mimicked using an exogenously added human LINGO-1-Fc fusion protein. Together these observations suggest that LINGO-1 has an important role in CNS biology.
Biogen was pretty quick (2005) to confirm that Lingo-1 antagonists could aid with remyelination:
Nature Neuroscience 8, 745 - 751 (2005)
Published online: 15 May 2005; | doi:10.1038/nn1460
LINGO-1 negatively regulates myelination by oligodendrocytes
Sha Mi1, Robert H Miller2, Xinhua Lee1, Martin L Scott1, Svetlane Shulag-Morskaya1, Zhaohui Shao1, Jufang Chang3, Greg Thill1, Melissa Levesque1, Mingdi Zhang1, Cathy Hession1, Dinah Sah1, Bruce Trapp4, Zhigang He3, Vincent Jung1, John M McCoy1 & R Blake Pepinsky1
1 Department of Discovery Biology, Biogen Idec, Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, USA.
2 Department of Neuroscience, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
3 Division of Neuroscience, Children's Hospital, Harvard Medical School, 320 Longwood Avenue, Boston, Massachusetts 02115, USA.
4 Department of Neuroscience, NC30, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
Correspondence should be addressed to Sha Mi firstname.lastname@example.org
The control of myelination by oligodendrocytes in the CNS is poorly understood. Here we show that LINGO-1 is an important negative regulator of this critical process. LINGO-1 is expressed in oligodendrocytes. Attenuation of its function by dominant-negative LINGO-1, LINGO-1 RNA-mediated interference (RNAi) or soluble human LINGO-1 (LINGO-1-Fc) leads to differentiation and increased myelination competence. Attenuation of LINGO-1 results in downregulation of RhoA activity, which has been implicated in oligodendrocyte differentiation. Conversely, overexpression of LINGO-1 leads to activation of RhoA and inhibition of oligodendrocyte differentiation and myelination. Treatment of oligodendrocyte and neuron cocultures with LINGO-1-Fc resulted in highly developed myelinated axons that have internodes and well-defined nodes of Ranvier. The contribution of LINGO-1 to myelination was verified in vivo through the analysis of LINGO-1 knockout mice. The ability to recapitulate CNS myelination in vitro using LINGO-1 antagonists and the in vivo effects seen in the LINGO-1 knockout indicate that LINGO-1 signaling may be critical for CNS myelination.
http://www.nature.com/neuro/journal/v8/ ... n1460.html
They then determined that inhibiting lingo would promote axonal outgrowth and improve recovery from spinal injury (2006):
Mol Cell Neurosci. 2006 Nov;33(3):311-20. Epub 2006 Sep 29.
LINGO-1 antagonist promotes functional recovery and axonal sprouting after spinal cord injury.
Ji B, Li M, Wu WT, Yick LW, Lee X, Shao Z, Wang J, So KF, McCoy JM, Pepinsky RB, Mi S, Relton JK.
Biogen Idec, Inc., 14 Cambridge Center, Cambridge, MA 02142, USA.
LINGO-1 is a CNS-specific protein and a functional component of the NgR1/p75/LINGO-1 and NgR1/TAJ(TROY)/LINGO-1 signaling complexes that mediate inhibition of axonal outgrowth. These receptor complexes mediate the axonal growth inhibitory effects of Nogo, myelin-associated glycoprotein (MAG) and oligodendrocyte-myelin glycoprotein (OMgp) via RhoA activation. Soluble LINGO-1 (LINGO-1-Fc), which acts as an antagonist of these pathways by blocking LINGO-1 binding to NgR1, was administered to rats after dorsal or lateral hemisection of the spinal cord. LINGO-1-Fc treatment significantly improved functional recovery, promoted axonal sprouting and decreased RhoA activation and increased oligodendrocyte and neuronal survival after either rubrospinal or corticospinal tract transection. These experiments demonstrate an important role for LINGO-1 in modulating axonal outgrowth in vivo and that treatment with LINGO-1-Fc can significantly enhance recovery after spinal cord injury.
In 2007, Biogen found that lingo-1 is an inhibitor of oligodendrocyte differentiation, not only when it is expressed by oligodendrocyte precursors, but also when expressed by axons:
NGF Regulates the Expression of Axonal LINGO-1 to Inhibit Oligodendrocyte Differentiation and Myelination
Xinhua Lee,1 Zhongshu Yang,1 Zhaohui Shao,1 Sheila S. Rosenberg,2 Melissa Levesque,1 R. Blake Pepinsky,1 Mengsheng Qiu,3 Robert H. Miller,4 Jonah R. Chan,2 and Sha Mi1
1Department of Discovery Biology, Biogen Idec, Cambridge, Massachusetts 02142, 2Department of Cell and Neurobiology, Zilkha Neurogenetic Institute, University of Southern California, Keck School of Medicine, Los Angeles, California 90033, 3Department of Anatomy and Neurobiology, University of Louisville, Louisville, Kentucky 40202, and 4Department of Neurosciences, Case School of Medicine, Cleveland, Ohio 44106
Correspondence should be addressed to either of the following: Dr. Jonah R. Chan, Zilkha Neurogenetic Institute, Keck School of Medicine at University of Southern California, Department of Cell and Neurobiology, 1501 San Pablo Street ZNI 421, Los Angeles, CA 90033, Email: email@example.com; or Dr. Sha Mi, Biogen Idec, Discovery Biology, 14 Cambridge Center, Cambridge, MA 02142, Email: firstname.lastname@example.org
Neurons and glia share a mutual dependence in establishing a functional relationship, and none is more evident than the process by which axons control myelination. Here, we identify LRR and Ig domain-containing, Nogo receptor-interacting protein (LINGO-1) as a potent axonal inhibitor of oligodendrocyte differentiation and myelination that is regulated by nerve growth factor and its cognate receptor TrkA in a dose-dependent manner. Whereas LINGO-1 expressed by oligodendrocyte progenitor cells was previously identified as an inhibitor of differentiation, we demonstrate that axonal expression of LINGO-1 inhibits differentiation with equal potency. Disruption of LINGO-1 on either cell type is sufficient to overcome the inhibitory action and promote differentiation and myelination, independent of axon diameter. Furthermore, these results were recapitulated in transgenic mice overexpressing the full length LINGO-1 under the neuronal promoter synapsin. Myelination was greatly inhibited in the presence of enforced axonal LINGO-1. The implications of these results relate specifically to the development of potential therapeutics targeting extrinsic growth factors that may regulate the axonal expression of modulators of oligodendrocyte development.
Also in 2007, a group in Japan found that Lingo-1, expressed on astrocytes, macrophages/microglia and neurones, by interacting with Nogo-A on oligodendrocytes, might modulate glial-neuronal interactions in demyelinating lesions of MS:
Neuropathol Appl Neurobiol. 2007 Feb;33(1):99-107.
TROY and LINGO-1 expression in astrocytes and macrophages/microglia in multiple sclerosis lesions.
Satoh J, Tabunoki H, Yamamura T, Arima K, Konno H.
Department of Bioinformatics, Meiji Pharmaceutical University, Tokyo, Japan. email@example.com
Nogo constitutes a family of neurite outgrowth inhibitors contributing to a failure of axonal regeneration in the adult central nervous system (CNS). Nogo-A is expressed exclusively on oligodendrocytes where Nogo-66 segment binds to Nogo receptor (NgR) expressed on neuronal axons. NgR signalling requires a coreceptor p75(NTR) or TROY in combination with an adaptor LINGO-1. To characterize the cell types expressing the NgR complex in the human CNS, we studied demyelinating lesions of multiple sclerosis (MS) brains by immunohistochemistry. TROY and LINGO-1 were identified in subpopulations of reactive astrocytes, macrophages/microglia and neurones but not in oligodendrocytes. TROY was up-regulated, whereas LINGO-1 was reduced in MS brains by Western blot. These results suggest that the ternary complex of NgR/TROY/LINGO-1 expressed on astrocytes, macrophages/microglia and neurones, by interacting with Nogo-A on oligodendrocytes, might modulate glial-neuronal interactions in demyelinating lesions of MS.
Again in 2007, Biogen found that a Lingo-1 antagonist promoted remyelination in good old EAE (we all hate the mouse studies, but nothing gets to human trials without a lot of mice dying first):
Nat Med. 2007 Oct;13(10):1228-33. Epub 2007 Sep 30.
LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis.
Mi S, Hu B, Hahm K, Luo Y, Kam Hui ES, Yuan Q, Wong WM, Wang L, Su H, Chu TH, Guo J, Zhang W, So KF, Pepinsky B, Shao Z, Graff C, Garber E, Jung V, Wu EX, Wu W.
Biogen Idec Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, USA. firstname.lastname@example.org
Demyelinating diseases, such as multiple sclerosis, are characterized by the loss of the myelin sheath around neurons, owing to inflammation and gliosis in the central nervous system (CNS). Current treatments therefore target anti-inflammatory mechanisms to impede or slow disease progression. The identification of a means to enhance axon myelination would present new therapeutic approaches to inhibit and possibly reverse disease progression. Previously, LRR and Ig domain-containing, Nogo receptor-interacting protein (LINGO-1) has been identified as an in vitro and in vivo negative regulator of oligodendrocyte differentiation and myelination. Here we show that loss of LINGO-1 function by Lingo1 gene knockout or by treatment with an antibody antagonist of LINGO-1 function leads to functional recovery from experimental autoimmune encephalomyelitis. This is reflected biologically by improved axonal integrity, as confirmed by magnetic resonance diffusion tensor imaging, and by newly formed myelin sheaths, as determined by electron microscopy. Antagonism of LINGO-1 or its pathway is therefore a promising approach for the treatment of demyelinating diseases of the CNS.
In 2009, Biogen confirmed that their anti-lingo drug was working to increase remyelination by inducing differentiation of oligodendrocyte precursor cells:
Ann Neurol. 2009 Mar;65(3):304-15.
Promotion of central nervous system remyelination by induced differentiation of oligodendrocyte precursor cells.
Mi S, Miller RH, Tang W, Lee X, Hu B, Wu W, Zhang Y, Shields CB, Zhang Y, Miklasz S, Shea D, Mason J, Franklin RJ, Ji B, Shao Z, Chédotal A, Bernard F, Roulois A, Xu J, Jung V, Pepinsky B.
Biogen Idec, Cambridge, MA 02142, USA. email@example.com
OBJECTIVE: Repair of demyelinated axons in diseases such as multiple sclerosis requires activation of the myelination program in existing or newly recruited oligodendrocyte precursor cells (OPCs). The control of OPC differentiation and initiation of myelination during repair is poorly understood. In this study, we test the ability of anti-LINGO-1 reagents to promote myelination in vitro and remyelination in the rodent adult central nervous system in vivo. METHODS: The effects of LINGO-1 antagonists on the differentiation of OPCs and the promotion of myelination has been assayed using a combination of coculture and slice culture preparations. Using three different animal models of demyelination and remyelination, we morphologically and functionally assessed the effects of LINGO-1 antagonists on OPC differentiation and myelin repair. RESULTS: The data indicate that in vitro treatment with antagonists of LINGO-1 promote OPC differentiation and myelination, whereas in vivo remyelination is accelerated in lysophosphatidylcholine- or cuprizone-induced demyelination. This remyelination is associated with enhanced OPC differentiation and functional recovery of conduction velocities in demyelinated axons. INTERPRETATION: Our studies demonstrate that LINGO-1 antagonism promotes OPC differentiation and remyelination, and suggest LINGO-1 functions as an inhibitor of OPC differentiation to retard central nervous system remyelination.
And now here we are, around 8 years later, with a drug in human trials. The patient in me says it has been painfully slow, but considering how slow it could be, this really isn't bad.