New Insights into the Roles of Nogo-A in CNS Biology and Diseases

Abstract

Nogos have become a hot topic for its well-known number Nogo-A's big role in clinical matters. It has been recognized that the expression of Nogo-A and the receptor NgR1 inhibit the neuron's growth after CNS injuries or the onset of the MS. The piling evidence supports the notion that the Nogo-A is also involved in the synaptic plasticity, which was shown to negatively regulate the strength of synaptic transmission. The occurrence of significant schizophrenia-like behavioral phenotypes in Nogo-A KO rats also added strong proof to this conclusion. This review mainly focuses on the structure of Nogo-A and its corresponding receptor-NgR1, its intra- and extra-cellular signaling, together with its major physiological functions such as regulation of migration and distribution and its related diseases like stroke, AD, ALS and so on.

Decreased Expression of α-Synuclein, Nogo-A and UCH-L1 in Patients with Schizophrenia: A Preliminary Serum Study

“…Postmortem and genetic studies have implicated Nogo expression levels and its chromosomal location (chromosome 2p16.1) in the etiology of schizophrenia 162526272829. In addition, in chromosome 22q11, which is also associated with schizophrenia, lays the Nogo-66 receptor NgR1 17. It was reported that knockout of the Nogo-A gene could cause specific behavioral abnormalities similar to schizophrenia-related endophenotypes, for instance deficient sensorimotor gating, disrupted latent inhibition, perseverative behavior and increased sensitivity to the locomotor stimulating effects of amphetamine 17.…”

“…In addition, in chromosome 22q11, which is also associated with schizophrenia, lays the Nogo-66 receptor NgR1 17. It was reported that knockout of the Nogo-A gene could cause specific behavioral abnormalities similar to schizophrenia-related endophenotypes, for instance deficient sensorimotor gating, disrupted latent inhibition, perseverative behavior and increased sensitivity to the locomotor stimulating effects of amphetamine 17. The result of our study with lower serum Nogo-A levels in patients with schizophrenia also supports the previous studies in explaining myelin dysfunction theory.…”

“…Myelin dysfunction is one of the strongly supported hypotheses for explaining pathogenesis of schizophrenia 16. Nogo-A is a necessary ligand for CNS construct at either beginning of the CNS building or later the maintenance in the adult, but at the same time an inhibitory factor to CNS recovery after injuries or disease, which mainly is expressed on the surface of the oligodendrocytes that myelinate the CNS neurons during development of the CNS, and may contribute to the neuron spreading direction and the neuron distribution pattern 17. This myelin hypothesis is supported by gene expression studies,181920 histopathology studies2122 and imaging studies 2324.…”

A Nogo-Like Signaling Perspective from Birth to Adulthood and in Old Age: Brain Expression Patterns of Ligands, Receptors and Modulators

“…The nerve-growth inhibitory ligand Nogo-A was first identified in CNS myelin in 1988 (Caroni and Schwab, 1988a , b ) and later shown to be expressed also in neurons (Chen et al, 2000 ; Josephson et al, 2001 ). Currently, known ligands, receptors, co-receptors, and modulators participating in Nogo-like signaling encompass some 20 proteins (Mironova and Giger, 2013 ; Schwab and Strittmatter, 2014 ; Sui et al, 2015 ; Seiler et al, 2016 ). Together, they regulate development, adult structural synaptic plasticity and memory (McGee et al, 2005 ; Mingorance-Le Meur et al, 2007 ; Giger et al, 2010 ; Akbik et al, 2013 ; Mironova and Giger, 2013 ; Nordgren et al, 2013 ; Schwab and Strittmatter, 2014 ; Karlsson et al, 2016 , 2017 ; Zagrebelsky et al, 2017 ), including appropriate motor learning (Zemmar et al, 2014 ).…”

“…The system also affects recovery from injury, such as axonal regeneration (Chen et al, 2017 ), and is involved in CNS reactions to injury and disease, including multiple sclerosis, schizophrenia, intracerebral tumors and stroke (Eslamboli et al, 2006 ; Cheatwood et al, 2008 ; Jung et al, 2011 ; Xiong et al, 2012 ; Willi and Schwab, 2013 ). Nogo-A can bind to Nogo receptor 1 (NgR1) through an extracellular loop, activating the NgR1 signaling complex (including coreceptors) resulting in nerve growth inhibition via the RhoA pathway, visualized in Figure 1 (Fournier et al, 2001 ; Niederöst et al, 2002 ; Sui et al, 2015 ). The signaling system has grown more complex as exemplified by the fact that Nogo-A can also bind to paired immunoglobulin-like receptor B (PirB), sphingosine-1-phosphate receptor 2 (S1PR2), and Syndecans (GrandPré et al, 2002 ; Atwal et al, 2008 ; Kempf et al, 2014 , 2017 ).…”