Can We Design a Nogo Receptor-Dependent Cellular Therapy to Target MS?

Kim, Min Joung; Kang, Jeonggyu; Theotokis, Paschalis; Grigoriadis, Nikolaos; Petratos, Steven

doi:10.3390/cells8010001

Cited by 24 publications

(10 citation statements)

References 126 publications

(178 reference statements)

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“…Additionally, gangliosides play a collaborative role in the signaling complex and have also been demonstrated to be important in preventing neuronal growth after spinal growth injury [80,81]. During neuroinflammation it has been demonstrated that NgR1-dependent signaling within spinal cord and optic nerve axons occurs through RhoA-GTP and the phosphorylation of the Rho-associated coiled-coil containing protein kinase 2 (ROCK II) to alter axonal transport and elicit neurodegeneration through downstream phosphorylation of the collapsin response mediator protein 2 (CRMP2) at the threonine 555 site located at its C-terminus [21,87]. Moreover, activation of NgR signaling through the binding of MAIFs present in extracellular myelin debris, can potentiate endogenous inhibitory effects on the maturation of oligodendroglial precursor cells (OPCs) and their recruitment around demyelinated plaques disrupting the remyelination process in progressive MS [77].…”

Section: Ngr Complex Signaling Pathways Interaction With Various Componentsmentioning

confidence: 99%

Novel contributors to B cell activation during inflammatory CNS demyelination; An oNGOing process

Damianidou¹,

Theotokis²,

Grigoriadis³

et al. 2022

Int. J. Med. Sci.

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Over the past two decades, the development of targeted immunotherapeutics for relapsing-remitting multiple sclerosis has been successfully orchestrated through the efficacious modulation of neuroinflammatory outcomes demonstrated in the experimental autoimmune encephalomyelitis (EAE) model. In this model, the focus of developing immunomodulatory therapeutics has been demonstrated through their effectiveness in modifying the pro-inflammatory Th1 and Th17-dependent neuropathological outcomes of demyelination, oligodendrocytopathy and axonal dystrophy. However, recent successful preclinical and clinical trials have advocated for the significance of B cell-dependent immunopathogenic responses and has led to the development of novel biologicals that target specific B cell phenotypes. In this context, a new molecule, B-cell activating factor (BAFF), has emerged as a positive regulator of B cell survival and differentiation functioning through various signaling pathways and potentiating the activity of various receptor complexes through pleiotropic means. One possible cognate receptor for BAFF includes the Nogo receptor (NgR) and its homologs, previously established as potent inhibitors of axonal regeneration during central nervous system (CNS) injury and disease. In this review we provide current evidence for BAFF-dependent signaling through the NgR multimeric complex, elucidating their association within the CNS compartment and underlying the importance of these potential pathogenic molecular regulators as possible therapeutic targets to limit relapse rates and potentially MS progression.

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Section: Ngr Complex Signaling Pathways Interaction With Various Componentsmentioning

confidence: 99%

Novel contributors to B cell activation during inflammatory CNS demyelination; An oNGOing process

Damianidou¹,

Theotokis²,

Grigoriadis³

et al. 2022

Int. J. Med. Sci.

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“…However, there is a lack of therapeutic approaches for secondary progressive MS (SPMS), a stage of the disease that follows RRMS. Moreover, available therapy options, which suppress or ablate the patient’s immune system, only slow disease progression but do not reverse neurological deficits [ 106 ]. Therefore, to improve treatment effectiveness and enhance patients’ quality of life, there is a pressing need for novel therapeutic approaches to restore neuronal function via promoting regeneration and remyelination.…”

Section: Nogo and Their Interacting Partners As Potential Therapeutic Targetsmentioning

confidence: 99%

The Implication of Reticulons (RTNs) in Neurodegenerative Diseases: From Molecular Mechanisms to Potential Diagnostic and Therapeutic Approaches

Kulczyńska-Przybik

Mroczko

Dulewicz

et al. 2021

IJMS

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Reticulons (RTNs) are crucial regulatory factors in the central nervous system (CNS) as well as immune system and play pleiotropic functions. In CNS, RTNs are transmembrane proteins mediating neuroanatomical plasticity and functional recovery after central nervous system injury or diseases. Moreover, RTNs, particularly RTN4 and RTN3, are involved in neurodegeneration and neuroinflammation processes. The crucial role of RTNs in the development of several neurodegenerative diseases, including Alzheimer’s disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), or other neurological conditions such as brain injury or spinal cord injury, has attracted scientific interest. Reticulons, particularly RTN-4A (Nogo-A), could provide both an understanding of early pathogenesis of neurodegenerative disorders and be potential therapeutic targets which may offer effective treatment or inhibit disease progression. This review focuses on the molecular mechanisms and functions of RTNs and their potential usefulness in clinical practice as a diagnostic tool or therapeutic strategy.

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“…This suggests that a gate in plasticity is lacking in the ngr1 −/− mice since the potent Nogo-A neurite outgrowth inhibitor expressed in mature oligodendrocytes in adulthood cannot limit the membrane-dependent dendritic or axonal varicosity formation. Therapeutics are being developed to target NgR1-dependent membrane interactions in various disease paradigms (for review see Petratos et al, 2012 ; Lee and Petratos, 2013 ; Lee et al, 2014 ; Kim et al, 2018 ). Therefore, it is important to dissect and define the precise mechanisms in which NgR1 can regulate plasticity at the axo-glial synapse.…”

Section: Nogo Receptor 1 (Ngr1) Regulates Neuronal Morphology and Synmentioning

confidence: 99%

That’s a Wrap! Molecular Drivers Governing Neuronal Nogo Receptor-Dependent Myelin Plasticity and Integrity

Petratos

Theotokis

Kim

et al. 2020

Front. Cell. Neurosci.

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Myelin is a dynamic membrane that is important for coordinating the fast propagation of action potentials along small or large caliber axons (0.1-10 µm) some of which extend the entire length of the spinal cord. Due to the heterogeneity of electrical and energy demands of the variable neuronal populations, the axo-myelinic and axo-glial interactions that regulate the biophysical properties of myelinated axons also vary in terms of molecular interactions at the membrane interfaces. An important topic of debate in neuroscience is how myelin is maintained and modified under neuronal control and how disruption of this control (due to disease or injury) can initiate and/or propagate neurodegeneration. One of the key molecular signaling cascades that have been investigated in the context of neural injury over the past two decades involves the myelin-associated inhibitory factors (MAIFs) that interact with Nogo receptor 1 (NgR1). Chief among the MAIF superfamily of molecules is a reticulon family protein, Nogo-A, that is established as a potent inhibitor of neurite sprouting and axon regeneration. However, an understated role for NgR1 is its ability to control axo-myelin interactions and Nogo-A specific ligand binding. These interactions may occur at axo-dendritic and axo-glial synapses regulating their functional and dynamic membrane domains. The current review provides a comprehensive analysis of how neuronal NgR1 can regulate myelin thickness and plasticity under normal and disease conditions. Specifically, we discuss how NgR1 plays an important role in regulating paranodal and juxtaparanodal domains through specific signal transduction cascades that are important for microdomain molecular architecture and action potential propagation. Potential therapeutics designed to target NgR1-dependent signaling during disease are being developed in animal models since interference with the involvement of the receptor may facilitate neurological recovery. Hence, the regulatory role played by NgR1 in the axo-myelinic interface is an important research field of clinical significance that requires comprehensive investigation.

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Can We Design a Nogo Receptor-Dependent Cellular Therapy to Target MS?

Cited by 24 publications

References 126 publications

Novel contributors to B cell activation during inflammatory CNS demyelination; An oNGOing process

Novel contributors to B cell activation during inflammatory CNS demyelination; An oNGOing process

The Implication of Reticulons (RTNs) in Neurodegenerative Diseases: From Molecular Mechanisms to Potential Diagnostic and Therapeutic Approaches

That’s a Wrap! Molecular Drivers Governing Neuronal Nogo Receptor-Dependent Myelin Plasticity and Integrity

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