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

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          Abstract

          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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          Most cited references118

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          Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth.

          The inhibitory activity associated with myelin is a major obstacle for successful axon regeneration in the adult mammalian central nervous system (CNS). In addition to myelin-associated glycoprotein (MAG) and Nogo-A, available evidence suggests the existence of additional inhibitors in CNS myelin. We show here that a glycosylphosphatidylinositol (GPI)-anchored CNS myelin protein, oligodendrocyte-myelin glycoprotein (OMgp), is a potent inhibitor of neurite outgrowth in cultured neurons. Like Nogo-A, OMgp contributes significantly to the inhibitory activity associated with CNS myelin. To further elucidate the mechanisms that mediate this inhibitory activity of OMgp, we screened an expression library and identified the Nogo receptor (NgR) as a high-affinity OMgp-binding protein. Cleavage of NgR and other GPI-linked proteins from the cell surface renders axons of dorsal root ganglia insensitive to OMgp. Introduction of exogenous NgR confers OMgp responsiveness to otherwise insensitive neurons. Thus, OMgp is an important inhibitor of neurite outgrowth that acts through NgR and its associated receptor complex. Interfering with the OMgp/NgR pathway may allow lesioned axons to regenerate after injury in vivo.
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            Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice.

            In vitro studies indicate a role for the LIM kinase family in the regulation of cofilin phosphorylation and actin dynamics. In addition, abnormal expression of LIMK-1 is associated with Williams syndrome, a mental disorder with profound deficits in visuospatial cognition. However, the in vivo function of this family of kinases remains elusive. Using LIMK-1 knockout mice, we demonstrate a significant role for LIMK-1 in vivo in regulating cofilin and the actin cytoskeleton. Furthermore, we show that the knockout mice exhibited significant abnormalities in spine morphology and in synaptic function, including enhanced hippocampal long-term potentiation. The knockout mice also showed altered fear responses and spatial learning. These results indicate that LIMK-1 plays a critical role in dendritic spine morphogenesis and brain function.
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              Functions of Nogo proteins and their receptors in the nervous system.

              The membrane protein Nogo-A was initially characterized as a CNS-specific inhibitor of axonal regeneration. Recent studies have uncovered regulatory roles of Nogo proteins and their receptors--in precursor migration, neurite growth and branching in the developing nervous system--as well as a growth-restricting function during CNS maturation. The function of Nogo in the adult CNS is now understood to be that of a negative regulator of neuronal growth, leading to stabilization of the CNS wiring at the expense of extensive plastic rearrangements and regeneration after injury. In addition, Nogo proteins interact with various intracellular components and may have roles in the regulation of endoplasmic reticulum (ER) structure, processing of amyloid precursor protein and cell survival.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                28 April 2021
                May 2021
                : 22
                : 9
                : 4630
                Affiliations
                [1 ]Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland; maciej.dulewicz@ 123456umb.edu.pl (M.D.); mroczko@ 123456umb.edu.pl (B.M.)
                [2 ]Department of Criminal Law and Criminology, Faculty of Law, University of Bialystok, 15-213 Bialystok, Poland; p.mroczko@ 123456uwb.edu.pl
                [3 ]Department of Biochemical Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
                Author notes
                Author information
                https://orcid.org/0000-0002-9889-3585
                https://orcid.org/0000-0002-7149-017X
                https://orcid.org/0000-0002-4075-8479
                Article
                ijms-22-04630
                10.3390/ijms22094630
                8125174
                33924890
                4c3e9f8f-165a-4df0-861d-1cdba4acd5b7
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 30 March 2021
                : 23 April 2021
                Categories
                Review

                Molecular biology
                reticulons,nogo proteins,neurodegenerative diseases,multiple sclerosis,amyotrophic lateral sclerosis,alzheimer’s disease

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