Novel implications of Lingo-1 and its signaling partners in schizophrenia

F Fernandez-Enright,J L Andrews,K A Newell,C Pantelis,X F Huang

doi:10.1038/tp.2013.121

F Fernandez-Enright, J L Andrews + Show 3 more

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https://doi.org/10.1038/tp.2013.121

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Abstract

Myelination and neurite outgrowth both occur during brain development, and their disturbance has been previously been implicated in the pathophysiology of schizophrenia. Leucine-rich repeat and immunoglobulin domain-containing protein (Lingo-1) is a potent negative regulator of axonal myelination and neurite extension. As co-factors of Lingo-1 signaling (Nogo receptor (NgR), With No Lysine (K) (WNK1) and Myelin transcription factor 1 (Myt1)) have been implicated in the genetics of schizophrenia, we explored for the first time the role of Lingo-1 signaling pathways in this disorder. Lingo-1 protein, together with its co-receptor and co-factor proteins NgR, tumor necrosis factor (TNF) receptor orphan Y (TROY), p75, WNK1 and Myt1, have never been explored in the pathogenesis of schizophrenia. We examined protein levels of Lingo-1, NgR, TROY, p75, WNK1, Myt1 and myelin basic protein (MBP) (as a marker of myelination) within the post-mortem dorsolateral prefrontal cortex (DLPFC) (37 schizophrenia patients versus 37 matched controls) and hippocampus (Cornu Ammonis, CA1 and CA3) (20 schizophrenia patients versus 20 matched controls from the same cohort). Both of these brain regions are highly disrupted in the schizophrenia pathophysiology. There were significant increases in Lingo-1 (P<0.001) and Myt1 (P=0.023) and a reduction in NgR (P<0.001) in the DLPFC in schizophrenia subjects compared with controls. There were also increases in both TROY (P=0.001) and WNK1 (P=0.011) in the CA1 of schizophrenia subjects and, in contrast to the DLPFC, there was an increase in NgR (P=0.006) in the CA3 of schizophrenia subjects compared with controls. No significant difference was reported for MBP levels (P>0.05) between the schizophrenia and control groups in the three tested regions. This is the first time that a study has shown altered Lingo-1 signaling in the schizophrenia brain. Our novel findings may present a direct application for the use of a Lingo-1 antagonist to complement current and future schizophrenia therapies.

Highlights

Schizophrenia is a severe neuropsychiatric disorder with an elusive etiology, thought to result from abnormal brain development during the first 3 decades of life.[1]
Within the dorsolateral prefrontal cortex (DLPFC), a significant 11.5% increase in Myt[1] difference increased to a 20% increase in Lingo-1 expression in expression was observed in schizophrenia compared with control the schizophrenia-only group compared with controls (F1,51 = 15.229; P o0.001; Supplementary Figure SF1A)
Unlike Lingo-1 expression, our study found Nogo receptor (NgR) expression levels to be decreased in the DLPFC of schizophrenia compared with control subjects (P o 0.001)

Summary

Introduction

Schizophrenia is a severe neuropsychiatric disorder with an elusive etiology, thought to result from abnormal brain development during the first 3 decades of life.[1]. Leucine-rich repeat and immunoglobulin domain-containing protein (Lingo-1), a transmembrane signaltransducing molecule selectively expressed on oligodendrocytes and neurons,[13] has been reported to be a potent negative regulator of oligodendrocyte differentiation, axonal integrity and myelination.[13,14] Its action notably involves the Nogo receptor (NgR) as a part of a co-receptor complex. NgR binds with either the p75 neurotrophin receptor or tumor necrosis factor (TNF) receptor orphan Y (TROY).[15,16,17] The resulting trimolecular receptor complex Lingo-1/NgR/p75 or Lingo-1/NgR/TROY activates Ras homolog gene family, member A (RhoA), initiating a cascade of intracellular molecular events resulting in collapse of growth cones, preventing further axonal growth and inhibiting myelination.[13,18] The existence of additional signaling co-factors has been suggested based on the absence of p75 and TROY on Lingo-1 containing neurons projecting to the spinal cord.[19]

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