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

Cells ◽  
2018 ◽  
Vol 8 (1) ◽  
pp. 1 ◽  
Author(s):  
Min Kim ◽  
Jung Kang ◽  
Paschalis Theotokis ◽  
Nikolaos Grigoriadis ◽  
Steven Petratos
Keyword(s):  
Small Molecules ◽  
Cellular Therapy ◽  
Unmet Need ◽  
Axonal Dystrophy ◽  
Signaling Mechanism ◽  
Current Review ◽  
Clinical Reality ◽  
Signaling Mechanisms ◽  
The Central Nervous System ◽  
Relapse Rates

The current landscape of therapeutics designed to treat multiple sclerosis (MS) and its pathological sequelae is saturated with drugs that modify disease course and limit relapse rates. While these small molecules and biologicals are producing profound benefits to patients with reductions in annualized relapse rates, the repair or reversal of demyelinated lesions with or without axonal damage, remains the principle unmet need for progressive forms of the disease. Targeting the extracellular pathological milieu and the signaling mechanisms that drive neurodegeneration are potential means to achieve neuroprotection and/or repair in the central nervous system of progressive MS patients. The Nogo-A receptor-dependent signaling mechanism has raised considerable interest in neurological disease paradigms since it can promulgate axonal transport deficits, further demyelination, and extant axonal dystrophy, thereby limiting remyelination. If specific therapeutic regimes could be devised to directly clear the Nogo-A-enriched myelin debris in an expedited manner, it may provide the necessary CNS environment for neurorepair to become a clinical reality. The current review outlines novel means to achieve neurorepair with biologicals that may be directed to sites of active demyelination.

scholarly journals Therapeutic Opportunities of Interleukin-33 in the Central Nervous System

2021 ◽  
Vol 12 ◽  
Author(s):  
Yun Sun ◽  
Yankai Wen ◽  
Luxi Wang ◽  
Liang Wen ◽  
Wendong You ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cerebrovascular Diseases ◽  
Receptor Complex ◽  
Functional Roles ◽  
Interleukin 33 ◽  
Current Review ◽  
Signaling Mechanisms ◽  
The Central Nervous System ◽  
Receptor Accessory Protein

Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is involved in various diseases. IL-33 exerts its effects via its heterodimeric receptor complex, which comprises suppression of tumorigenicity 2 (ST2) and the IL-1 receptor accessory protein (IL-1RAP). Increasing evidence has demonstrated that IL-33/ST2 signaling plays diverse but crucial roles in the homeostasis of the central nervous system (CNS) and the pathogenesis of CNS diseases, including neurodegenerative diseases, cerebrovascular diseases, infection, trauma, and ischemic stroke. In the current review, we focus on the functional roles and cellular signaling mechanisms of IL-33 in the CNS and evaluate the potential for diagnostic and therapeutic applications.

scholarly journals BDNF-induced recruitment of TrkB receptor into neuronal lipid rafts

2004 ◽  
Vol 167 (6) ◽  
pp. 1205-1215 ◽  
Author(s):  
Shingo Suzuki ◽  
Tadahiro Numakawa ◽  
Kazuhiro Shimazu ◽  
Hisatsugu Koshimizu ◽  
Tomoko Hara ◽  
...  
Keyword(s):  
Lipid Rafts ◽  
Plasma Membranes ◽  
Hippocampal Slices ◽  
Synaptic Response ◽  
Signaling Mechanism ◽  
Synaptic Modulation ◽  
Signaling Mechanisms ◽  
The Central Nervous System ◽  
Trk Inhibitors

Brain-derived neurotrophic factor (BDNF) plays an important role in synaptic plasticity but the underlying signaling mechanisms remain unknown. Here, we show that BDNF rapidly recruits full-length TrkB (TrkB-FL) receptor into cholesterol-rich lipid rafts from nonraft regions of neuronal plasma membranes. Translocation of TrkB-FL was blocked by Trk inhibitors, suggesting a role of TrkB tyrosine kinase in the translocation. Disruption of lipid rafts by depleting cholesterol from cell surface blocked the ligand-induced translocation. Moreover, disruption of lipid rafts prevented potentiating effects of BDNF on transmitter release in cultured neurons and synaptic response to tetanus in hippocampal slices. In contrast, lipid rafts are not required for BDNF regulation of neuronal survival. Thus, ligand-induced TrkB translocation into lipid rafts may represent a signaling mechanism selective for synaptic modulation by BDNF in the central nervous system.

Neuropeptides in Alzheimer’s Disease: An Update

2019 ◽  
Vol 16 (6) ◽  
pp. 544-558 ◽  
Author(s):  
Carla Petrella ◽  
Maria Grazia Di Certo ◽  
Christian Barbato ◽  
Francesca Gabanella ◽  
Massimo Ralli ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Potential Role ◽  
Brain Distribution ◽  
Brain Areas ◽  
Small Proteins ◽  
Current Review ◽  
The Central Nervous System ◽  
Available Information

Neuropeptides are small proteins broadly expressed throughout the central nervous system, which act as neurotransmitters, neuromodulators and neuroregulators. Growing evidence has demonstrated the involvement of many neuropeptides in both neurophysiological functions and neuropathological conditions, among which is Alzheimer’s disease (AD). The role exerted by neuropeptides in AD is endorsed by the evidence that they are mainly neuroprotective and widely distributed in brain areas responsible for learning and memory processes. Confirming this point, it has been demonstrated that numerous neuropeptide-containing neurons are pathologically altered in brain areas of both AD patients and AD animal models. Furthermore, the levels of various neuropeptides have been found altered in both Cerebrospinal Fluid (CSF) and blood of AD patients, getting insights into their potential role in the pathophysiology of AD and offering the possibility to identify novel additional biomarkers for this pathology. We summarized the available information about brain distribution, neuroprotective and cognitive functions of some neuropeptides involved in AD. The main focus of the current review was directed towards the description of clinical data reporting alterations in neuropeptides content in both AD patients and AD pre-clinical animal models. In particular, we explored the involvement in the AD of Thyrotropin-Releasing Hormone (TRH), Cocaine- and Amphetamine-Regulated Transcript (CART), Cholecystokinin (CCK), bradykinin and chromogranin/secretogranin family, discussing their potential role as a biomarker or therapeutic target, leaving the dissertation of other neuropeptides to previous reviews.

scholarly journals Targeted axonal import (TAxI) peptide delivers functional proteins into spinal cord motor neurons after peripheral administration

2016 ◽  
Vol 113 (9) ◽  
pp. 2514-2519 ◽  
Author(s):  
Drew L. Sellers ◽  
Jamie M. Bergen ◽  
Russell N. Johnson ◽  
Heidi Back ◽  
John M. Ravits ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Motor Neurons ◽  
Unmet Need ◽  
Nerve Roots ◽  
Biologic Drugs ◽  
Administration Routes ◽  
Macromolecular Drugs ◽  
The Central Nervous System ◽  
Clinical Potential

A significant unmet need in treating neurodegenerative disease is effective methods for delivery of biologic drugs, such as peptides, proteins, or nucleic acids into the central nervous system (CNS). To date, there are no operative technologies for the delivery of macromolecular drugs to the CNS via peripheral administration routes. Using an in vivo phage-display screen, we identify a peptide, targeted axonal import (TAxI), that enriched recombinant bacteriophage accumulation and delivered protein cargo into spinal cord motor neurons after intramuscular injection. In animals with transected peripheral nerve roots, TAxI delivery into motor neurons after peripheral administration was inhibited, suggesting a retrograde axonal transport mechanism for delivery into the CNS. Notably, TAxI-Cre recombinase fusion proteins induced selective recombination and tdTomato-reporter expression in motor neurons after intramuscular injections. Furthermore, TAxI peptide was shown to label motor neurons in the human tissue. The demonstration of a nonviral-mediated delivery of functional proteins into the spinal cord establishes the clinical potential of this technology for minimally invasive administration of CNS-targeted therapeutics.

scholarly journals A PINCH-1–Smurf1 signaling axis mediates mechano-regulation of BMPR2 and stem cell differentiation

2019 ◽  
Vol 218 (11) ◽  
pp. 3773-3794
Author(s):  
Ling Guo ◽  
Rong Wang ◽  
Kuo Zhang ◽  
Jifan Yuan ◽  
Jiaxin Wang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Differentiation ◽  
Bmp Signaling ◽  
Signaling Mechanism ◽  
Ubiquitin Protein Ligase ◽  
Signaling Mechanisms ◽  
Morphogenetic Protein ◽  
Signaling Axis ◽  
Fate Decision

Mechano-environment plays multiple critical roles in the control of mesenchymal stem cell (MSC) fate decision, but the underlying signaling mechanisms remain undefined. We report here a signaling axis consisting of PINCH-1, SMAD specific E3 ubiquitin protein ligase 1 (Smurf1), and bone morphogenetic protein type 2 receptor (BMPR2) that links mechano-environment to MSC fate decision. PINCH-1 interacts with Smurf1, which inhibits the latter from interacting with BMPR2 and consequently suppresses BMPR2 degradation, resulting in augmented BMP signaling and MSC osteogenic differentiation (OD). Extracellular matrix (ECM) stiffening increases PINCH-1 level and consequently activates this signaling axis. Depletion of PINCH-1 blocks stiff ECM-induced BMP signaling and OD, whereas overexpression of PINCH-1 overrides signals from soft ECM and promotes OD. Finally, perturbation of either Smurf1 or BMPR2 expression is sufficient to block the effects of PINCH-1 on BMP signaling and MSC fate decision. Our findings delineate a key signaling mechanism through which mechano-environment controls BMPR2 level and MSC fate decision.

scholarly journals Neurological Syndromes Associated with Anti-GAD Antibodies

2020 ◽  
Vol 21 (10) ◽  
pp. 3701 ◽  
Author(s):  
Maëlle Dade ◽  
Giulia Berzero ◽  
Cristina Izquierdo ◽  
Marine Giry ◽  
Marion Benazra ◽  
...  
Keyword(s):  
Unmet Need ◽  
Acid Decarboxylase ◽  
Gamma Aminobutyric Acid ◽  
Gad Antibodies ◽  
Intracellular Enzyme ◽  
Inhibitory Neurotransmitter ◽  
Predictors Of Response ◽  
Physiologic Function ◽  
The Central Nervous System ◽  
Relative Rarity

Glutamic acid decarboxylase (GAD) is an intracellular enzyme whose physiologic function is the decarboxylation of glutamate to gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter within the central nervous system. GAD antibodies (Ab) have been associated with multiple neurological syndromes, including stiff-person syndrome, cerebellar ataxia, and limbic encephalitis, which are all considered to result from reduced GABAergic transmission. The pathogenic role of GAD Ab is still debated, and some evidence suggests that GAD autoimmunity might primarily be cell-mediated. Diagnosis relies on the detection of high titers of GAD Ab in serum and/or in the detection of GAD Ab in the cerebrospinal fluid. Due to the relative rarity of these syndromes, treatment schemes and predictors of response are poorly defined, highlighting the unmet need for multicentric prospective trials in this population. Here, we reviewed the main clinical characteristics of neurological syndromes associated with GAD Ab, focusing on pathophysiologic mechanisms.

scholarly journals THE ROLE OF SYNAPSIN I IN INTRACELLULAR SIGNALING MECHANISMS UNDERLIES EXERCISE-INDUCED IMPROVEMENT IN SOCIAL MEMORY: A SYSTEMATIC REVIEW

2017 ◽  
Vol 10 (9) ◽  
pp. 88
Author(s):  
Ria Margiana ◽  
Akmal Primadian Suprapto
Keyword(s):  
Cell Signaling ◽  
Intracellular Signaling ◽  
Laboratory Experiments ◽  
Biological Function ◽  
Social Memory ◽  
Synapsin I ◽  
Signaling Mechanism ◽  
Signaling Mechanisms ◽  
Exercise Induced

  Objective: Intracellular signaling mechanism is an important biological function, as scholars continue to seek new ways of improving social memory. Researchers have conducted several studies on the role of synapsin I in intracellular signaling mechanism. This study assessed the empirical evidence that shows the role of synapsin I in intracellular signaling mechanism with the aim of achieving exercise-induced improvement in social memory.Methods: Nine previously conducted researches were reviewed in this paper. The included studies were controlled laboratory experiments involving mice as the subjects.Results: Although the studies included were done in different timelines, the researchers agreed in unison that synapsin I plays a crucial role in cell signaling. The outcome of the practical studies was vital in understanding function and physiology of human cells, which is fundamental in science and human anatomy.Conclusion: In particular, the findings shows how exercise can improve social memory by triggering the intracellular signaling mechanism. The limited number of studies addressing the topic of intracellular cell signaling suggests that more study is needed to provide more evidence on the issue.

Relapse rates and long-term outcome in primary angiitis of the central nervous system

2019 ◽  
Vol 266 (6) ◽  
pp. 1481-1489 ◽  
Author(s):  
Simon Schuster ◽  
Ann-Kathrin Ozga ◽  
Jan-Patrick Stellmann ◽  
Milani Deb-Chatterji ◽  
Vivien Häußler ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Primary Angiitis ◽  
The Central Nervous System ◽  
Relapse Rates

scholarly journals Targeting the TR4 nuclear receptor-mediated lncTASR/AXL signaling with tretinoin increases the sunitinib sensitivity to better suppress the RCC progression

Oncogene ◽  
2019 ◽  
Vol 39 (3) ◽  
pp. 530-545 ◽  
Author(s):  
Hangchuan Shi ◽  
Yin Sun ◽  
Miao He ◽  
Xiong Yang ◽  
Michiaki Hamada ◽  
...  
Keyword(s):  
Small Molecules ◽  
Nuclear Receptor ◽  
Preclinical Study ◽  
First Line ◽  
Novel Therapy ◽  
Signaling Mechanism ◽  
First Line Therapy ◽  
Line Therapy ◽  
The Stability

Abstract Renal cell carcinoma (RCC) is one of the most lethal urological tumors. Using sunitinib to improve the survival has become the first-line therapy for metastatic RCC patients. However, the occurrence of sunitinib resistance in the clinical application has curtailed its efficacy. Here we found TR4 nuclear receptor might alter the sunitinib resistance to RCC via altering the TR4/lncTASR/AXL signaling. Mechanism dissection revealed that TR4 could modulate lncTASR (ENST00000600671.1) expression via transcriptional regulation, which might then increase AXL protein expression via enhancing the stability of AXL mRNA to increase the sunitinib resistance in RCC. Human clinical surveys also linked the expression of TR4, lncTASR, and AXL to the RCC survival, and results from multiple RCC cell lines revealed that targeting this newly identified TR4-mediated signaling with small molecules, including tretinoin, metformin, or TR4-shRNAs, all led to increase the sunitinib sensitivity to better suppress the RCC progression, and our preclinical study using the in vivo mouse model further proved tretinoin had a better synergistic effect to increase sunitinib sensitivity to suppress RCC progression. Future successful clinical trials may help in the development of a novel therapy to better suppress the RCC progression.

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