LINGO-1 antagonist promotes functional recovery and axonal sprouting after spinal cord injury.
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.
Ji
Benxiu
B
Biogen Idec, Inc., 14 Cambridge Center, Cambridge, MA 02142, USA.
Li
Mingwei
M
Wu
Wu-Tian
WT
Yick
Leung-Wah
LW
Lee
Xinhua
X
Shao
Zhaohui
Z
Wang
Joy
J
So
Kwok-Fai
KF
McCoy
John M
JM
Pepinsky
R Blake
RB
Mi
Sha
S
Relton
Jane K
JK
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001369:Axons / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005552:Forelimb / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D009416:Nerve Regeneration / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D038081:Organogenesis / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D020127:Recovery of Function / Q000187:drug effects*; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
C482293:LINGO1 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; C488416:Tubb3 protein, rat; D014404:Tubulin; D048670:MAP Kinase Kinase 4; D053148:Caspase 3; D020742:rhoA GTP-Binding Protein