Novel implications of Lingo-1 and its signaling partners in schizophrenia.
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.
1] Centre for Translational Neuroscience, Illawarra Health and Medical Research Institute, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, Australia [2] Schizophrenia Research Institute, Darlinghurst, NSW, Australia.
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Fernandez-Enright
1] Centre for Translational Neuroscience, Illawarra Health and Medical Research Institute, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, Australia [2] Schizophrenia Research Institute, Darlinghurst, NSW, Australia.
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Andrews
1] Centre for Translational Neuroscience, Illawarra Health and Medical Research Institute, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, Australia [2] Schizophrenia Research Institute, Darlinghurst, NSW, Australia.
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Newell
Department of Psychiatry, Melbourne Neuropsychiatry Centre, University of Melbourne and Melbourne Health, Melbourne, VIC, Australia.
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Pantelis
1] Centre for Translational Neuroscience, Illawarra Health and Medical Research Institute, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, Australia [2] Schizophrenia Research Institute, Darlinghurst, NSW, Australia.
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Huang
D000328:Adult; D000368:Aged; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000502:physiology*; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology; D012559:Schizophrenia / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014015:Tissue Banks
C482293:LINGO1 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins