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Nogo-A and its functions beyond axonal inhibition: the controversial role of Nogo-A in Parkinson's disease.

Seiler S, Widmer HR - Neural Regen Res (2015)

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Neurocenter and Regenerative Neuroscience Cluster, University Hospital Bern, Switzerland University of Bern, Inselspital, Berne, Switzerland ; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.

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Nogo-A belongs to the reticulon family (RTN4) and is generally assumed to be one of the most potent myelin associated neurite outgrowth inhibitors in the central nervous system (CNS)... Together with other inhibitors such as the myelin associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp), several semaphorins and ephrins as well as chondriotin sulphate proteoglycans, Nogo-A contributes to a nonpermissive environment in the brain and spinal cord... Based on their seminal observation that neurons grown in close proximity to CNS derived oligodendrocytes showed a robust decrease in neurite outgrowth and number of processes, Schwab and Caroni (1988) postulated for nonpermissive substrate properties present in the CNS myelin... In addition, we identified subpopulations of these co-localizing cells as DAergic neurons projecting to the striatum... In line with this notion, in a rat model of PD, the number of nigral Nogo-A positive neurons was significantly reduced both 1 week and 1 month after the 6-OHDA lesions... This hints to the idea that other factors compensate for the loss of Nogo-A for example Nogo-B, MAG or OMgp (Teng and Tang, 2005)... Blocking of LINGO-1 resulted in increased EGFR levels and increased survival of DAergic neurons (Mi et al., 2013)... Moreover, LINGO-1 knock-out mice showed increased DAergic neuron survival and reduced behavioral abnormalities compared to wild type animals (Inoue et al., 2007)... Two clinical studies accomplished in China and Germany, however, were unable to find a significant correlation of LINGO-1 and risk of PD... Recently, we demonstrated that antagonization of the NgR1 resulted in significantly increased number and morphological complexity of cultured ventral mesencephalic DAergic neurons... We furthermore observed a larger culture volume of organotypic cultures after NgR1 antagonization, hinting to the idea that this treatment approach goes beyond direct effects on DAergic neurons (Seiler et al., 2013)... Indeed, Teng and co-workers reported that Nogo-A neutralization resulted in an up-regulation of growth factors such as brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor as well as growth-related proteins such as growth associated protein 43 (Teng and Tang, 2005)... Taken together, the role and involvement of Nogo-A in PD is just beginning to evolve... Even though none of the Nogo-A signaling genes has been associated with PD, results from animal studies show that DAergic neurons co-expressing Nogo-A survive better in the later course of PD as well as more pronounced DAergic cell death in PD... Yet, if and how Nogo-A protects DAergic neurons from toxic insults and if there are other myelin associated proteins that act through the NgR1 complex as negative regulator of DAergic neuron survival needs to be further investigated.

No MeSH data available.


Related in: MedlinePlus

Schematic drawing of the functions of Nogo-A during development and/or in the adult brain.Nogo-A not only inhibits axonal outgrowth but also regulates dendritic arborization and oligodendrocyte myelin formation during development (left circle) and controls long term depression (LTP) and short term memory formation in the adult brain (right circle). Moreover, Nogo-A modulates synaptic plasticity, cell migration, plasticity and stem cell survival and proliferation throughout life (middle circle).
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Figure 1: Schematic drawing of the functions of Nogo-A during development and/or in the adult brain.Nogo-A not only inhibits axonal outgrowth but also regulates dendritic arborization and oligodendrocyte myelin formation during development (left circle) and controls long term depression (LTP) and short term memory formation in the adult brain (right circle). Moreover, Nogo-A modulates synaptic plasticity, cell migration, plasticity and stem cell survival and proliferation throughout life (middle circle).

Mentions: Nogo-A has several ligand domains that interact with different receptors. One of these ligand domains is the so called Nogo-66 domain that binds to the Nogo-receptor 1 (NgR1). NgR1 is a glycosylphasphatidylinositol anchored membrane protein, which does not contain a transmembrane domain and needs therefore other proteins to transfer the signal further into the cytosol. Thus, NgR1 forms a complex with Leucine rich repeat and Ig domain containing 1 (LINGO-1) and tumor necrosis factor family member (TROY) and/or low affinity nerve growth factor receptor (p75). p75 is cleaved sequentially upon activation by alpha and gamma secretase thereby releasing an intracellular signaling peptide that activates the Rho GTPase pathway, which leads to inhibition of axonal growth (Saha et al., 2014). On the other hand, Nogo-66 can bind to the paired immunoglobulin-like receptor (PirB), however, its mechanisms are not well investigated. Another Nogo-A ligand domain is the so called Δ–20 domain, which binds to the sphingosine-1-phosphate receptor 2 that also leads to activation of the Rho GTPase pathway (Schwab and Strittmatter, 2014). Although Nogo-A signals through different receptors, all pathways converge into the Rho GTPase pathway, yet, Nogo-A causes different effects (Figure 1).


Nogo-A and its functions beyond axonal inhibition: the controversial role of Nogo-A in Parkinson's disease.

Seiler S, Widmer HR - Neural Regen Res (2015)

Schematic drawing of the functions of Nogo-A during development and/or in the adult brain.Nogo-A not only inhibits axonal outgrowth but also regulates dendritic arborization and oligodendrocyte myelin formation during development (left circle) and controls long term depression (LTP) and short term memory formation in the adult brain (right circle). Moreover, Nogo-A modulates synaptic plasticity, cell migration, plasticity and stem cell survival and proliferation throughout life (middle circle).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4590229&req=5

Figure 1: Schematic drawing of the functions of Nogo-A during development and/or in the adult brain.Nogo-A not only inhibits axonal outgrowth but also regulates dendritic arborization and oligodendrocyte myelin formation during development (left circle) and controls long term depression (LTP) and short term memory formation in the adult brain (right circle). Moreover, Nogo-A modulates synaptic plasticity, cell migration, plasticity and stem cell survival and proliferation throughout life (middle circle).
Mentions: Nogo-A has several ligand domains that interact with different receptors. One of these ligand domains is the so called Nogo-66 domain that binds to the Nogo-receptor 1 (NgR1). NgR1 is a glycosylphasphatidylinositol anchored membrane protein, which does not contain a transmembrane domain and needs therefore other proteins to transfer the signal further into the cytosol. Thus, NgR1 forms a complex with Leucine rich repeat and Ig domain containing 1 (LINGO-1) and tumor necrosis factor family member (TROY) and/or low affinity nerve growth factor receptor (p75). p75 is cleaved sequentially upon activation by alpha and gamma secretase thereby releasing an intracellular signaling peptide that activates the Rho GTPase pathway, which leads to inhibition of axonal growth (Saha et al., 2014). On the other hand, Nogo-66 can bind to the paired immunoglobulin-like receptor (PirB), however, its mechanisms are not well investigated. Another Nogo-A ligand domain is the so called Δ–20 domain, which binds to the sphingosine-1-phosphate receptor 2 that also leads to activation of the Rho GTPase pathway (Schwab and Strittmatter, 2014). Although Nogo-A signals through different receptors, all pathways converge into the Rho GTPase pathway, yet, Nogo-A causes different effects (Figure 1).

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Neurocenter and Regenerative Neuroscience Cluster, University Hospital Bern, Switzerland University of Bern, Inselspital, Berne, Switzerland ; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Nogo-A belongs to the reticulon family (RTN4) and is generally assumed to be one of the most potent myelin associated neurite outgrowth inhibitors in the central nervous system (CNS)... Together with other inhibitors such as the myelin associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp), several semaphorins and ephrins as well as chondriotin sulphate proteoglycans, Nogo-A contributes to a nonpermissive environment in the brain and spinal cord... Based on their seminal observation that neurons grown in close proximity to CNS derived oligodendrocytes showed a robust decrease in neurite outgrowth and number of processes, Schwab and Caroni (1988) postulated for nonpermissive substrate properties present in the CNS myelin... In addition, we identified subpopulations of these co-localizing cells as DAergic neurons projecting to the striatum... In line with this notion, in a rat model of PD, the number of nigral Nogo-A positive neurons was significantly reduced both 1 week and 1 month after the 6-OHDA lesions... This hints to the idea that other factors compensate for the loss of Nogo-A for example Nogo-B, MAG or OMgp (Teng and Tang, 2005)... Blocking of LINGO-1 resulted in increased EGFR levels and increased survival of DAergic neurons (Mi et al., 2013)... Moreover, LINGO-1 knock-out mice showed increased DAergic neuron survival and reduced behavioral abnormalities compared to wild type animals (Inoue et al., 2007)... Two clinical studies accomplished in China and Germany, however, were unable to find a significant correlation of LINGO-1 and risk of PD... Recently, we demonstrated that antagonization of the NgR1 resulted in significantly increased number and morphological complexity of cultured ventral mesencephalic DAergic neurons... We furthermore observed a larger culture volume of organotypic cultures after NgR1 antagonization, hinting to the idea that this treatment approach goes beyond direct effects on DAergic neurons (Seiler et al., 2013)... Indeed, Teng and co-workers reported that Nogo-A neutralization resulted in an up-regulation of growth factors such as brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor as well as growth-related proteins such as growth associated protein 43 (Teng and Tang, 2005)... Taken together, the role and involvement of Nogo-A in PD is just beginning to evolve... Even though none of the Nogo-A signaling genes has been associated with PD, results from animal studies show that DAergic neurons co-expressing Nogo-A survive better in the later course of PD as well as more pronounced DAergic cell death in PD... Yet, if and how Nogo-A protects DAergic neurons from toxic insults and if there are other myelin associated proteins that act through the NgR1 complex as negative regulator of DAergic neuron survival needs to be further investigated.

No MeSH data available.


Related in: MedlinePlus