scholarly journals Bring it back, bring it back, don't take it away from me – the sorting receptor RER1

2020 ◽  
Vol 133 (17) ◽  
pp. jcs231423
Author(s):  
Wim Annaert ◽  
Christoph Kaether
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Biology ◽  
Mammalian Cells ◽  
Future Directions ◽  
Binding Motifs ◽  
Sorting Receptor ◽  
Intermediate Compartment ◽  
The Brain

ABSTRACTThe quote “bring it back, bring it back, don't take it away from me” from Queen's Love of my life describes the function of the sorting receptor RER1, a 23 kDa protein with four transmembrane domains (TMDs) that localizes to the intermediate compartment and the cis-Golgi. From there it returns escaped proteins that are not supposed to leave the endoplasmic reticulum (ER) back to it. Unique about RER1 is its ability to recognize its ligands through binding motifs in TMDs. Among its substrates are ER-resident proteins, as well as unassembled subunits of multimeric complexes that are retrieved back into the ER, this way guarding the full assembly of their respective complexes. The basic mechanisms for RER1-dependent retrieval have been already elucidated some years ago in yeast. More recently, several important cargoes of RER1 have been described in mammalian cells, and the in vivo role of RER1 is being unveiled by using mouse models. In this Review, we give an overview of the cell biology of RER1 in different models, discuss its controversial role in the brain and provide an outlook on future directions for RER1 research.

scholarly journals Identification of Mammalian Sds3 as an Integral Component of the Sin3/Histone Deacetylase Corepressor Complex

2002 ◽  
Vol 22 (8) ◽  
pp. 2743-2750 ◽  
Author(s):  
Leila Alland ◽  
Gregory David ◽  
Hong Shen-Li ◽  
Jason Potes ◽  
Rebecca Muhle ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Cell Biology ◽  
Mammalian Cells ◽  
Chromatin Modification ◽  
Eukaryotic Cell ◽  
Hdac Activity ◽  
Corepressor Complex ◽  
Local Recruitment

ABSTRACT Silencing of gene transcription involves local chromatin modification achieved through the local recruitment of large multiprotein complexes containing histone deacetylase (HDAC) activity. The mammalian corepressors mSin3A and mSin3B have been shown to play a key role in this process by tethering HDACs 1 and 2 to promoter-bound transcription factors. Similar mechanisms appear to be operative in yeast, in which epistasis experiments have established that the mSin3 and HDAC orthologs (SIN3 and RPD3), along with a novel protein, SDS3, function in the same repressor pathway. Here, we report the identification of a component of the mSin3-HDAC complex that bears homology to yeast SDS3, physically associates with mSin3 proteins in vivo, represses transcription in a manner that is partially dependent on HDAC activity, and enables HDAC1 catalytic activity in vivo. That key physical and functional properties are also shared by yeast SDS3 underscores the central role of the Sin3-HDAC-Sds3 complex in eukaryotic cell biology, and the discovery of mSds3 in mammalian cells provides a new avenue for modulating the activity of this complex in human disease.

Alcohol Use Disorder

2018 ◽  
Author(s):  
Igor Ponomarev
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Critical Discussion ◽  
Epigenetic Mechanisms ◽  
Future Directions ◽  
Clinically Significant ◽  
Early Life Exposures ◽  
The Brain ◽  
Epigenetic Research

Alcohol use disorder (AUD) is characterized by clinically significant impairments in health and social function. Epigenetic mechanisms of gene regulation may provide an attractive explanation for how early life exposures to alcohol contribute to the development of AUD and exert lifelong effects on the brain. This chapter provides a critical discussion of the role of epigenetic mechanisms in AUD etiology and the potential of epigenetic research to improve diagnosis, evaluate risks for alcohol-induced pathologies, and promote development of novel therapies for the prevention and treatment of AUD. Challenges of the current epigenetic approaches and future directions are also discussed.

scholarly journals Role of interleukins in the pathogenesis of pulmonary fibrosis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yi Xin She ◽  
Qing Yang Yu ◽  
Xiao Xiao Tang
Keyword(s):  
Pulmonary Fibrosis ◽  
Therapeutic Strategy ◽  
Future Directions ◽  
Regulation Mechanisms ◽  
Underlying Mechanisms ◽  
Multiple Cells ◽  
The Relationship

AbstractInterleukins, a group of cytokines participating in inflammation and immune response, are proved to be involved in the formation and development of pulmonary fibrosis. In this article, we reviewed the relationship between interleukins and pulmonary fibrosis from the clinical, animal, as well as cellular levels, and discussed the underlying mechanisms in vivo and in vitro. Despite the effects of interleukin-targeted treatment on experimental pulmonary fibrosis, clinical applications are lacking and unsatisfactory. We conclude that intervening in one type of interleukins with similar functions in IPF may not be enough to stop the development of fibrosis as it involves a complex network of regulation mechanisms. Intervening interleukins combined with other existing therapy or targeting interleukins affecting multiple cells/with different functions at the same time may be one of the future directions. Furthermore, the intervention time is critical as some interleukins play different roles at different stages. Further elucidation on these aspects would provide new perspectives on both the pathogenesis mechanism, as well as the therapeutic strategy and drug development.

scholarly journals The Role of Pre-Clinical 3-Dimensional Models of Osteosarcoma

2020 ◽  
Vol 21 (15) ◽  
pp. 5499
Author(s):  
Hannah L. Smith ◽  
Stephen A. Beers ◽  
Juliet C. Gray ◽  
Janos M. Kanczler
Keyword(s):  
Three Dimensional ◽  
Chorioallantoic Membrane ◽  
3D Models ◽  
In Ovo ◽  
Future Directions ◽  
3 Dimensional ◽  
In Vivo Animal Models

Treatment for osteosarcoma (OS) has been largely unchanged for several decades, with typical therapies being a mixture of chemotherapy and surgery. Although therapeutic targets and products against cancer are being continually developed, only a limited number have proved therapeutically active in OS. Thus, the understanding of the OS microenvironment and its interactions are becoming more important in developing new therapies. Three-dimensional (3D) models are important tools in increasing our understanding of complex mechanisms and interactions, such as in OS. In this review, in vivo animal models, in vitro 3D models and in ovo chorioallantoic membrane (CAM) models, are evaluated and discussed as to their contribution in understanding the progressive nature of OS, and cancer research. We aim to provide insight and prospective future directions into the potential translation of 3D models in OS.

scholarly journals The role of CYP2D in rat brain in methamphetamine-induced striatal dopamine and serotonin release and behavioral sensitization

2021 ◽  
Author(s):  
Marlaina R. Stocco ◽  
Ahmed A. El-Sherbeni ◽  
Bin Zhao ◽  
Maria Novalen ◽  
Rachel F. Tyndale
Keyword(s):  
Neurotransmitter Release ◽  
Behavioral Sensitization ◽  
Serotonin Release ◽  
Striatal Dopamine ◽  
Irreversible Inhibitor ◽  
Drug Concentrations ◽  
Metabolite Concentrations ◽  
The Brain

Abstract Rationale Cytochrome P450 2D (CYP2D) enzymes metabolize many addictive drugs, including methamphetamine. Variable CYP2D metabolism in the brain may alter CNS drug/metabolite concentrations, consequently affecting addiction liability and neuropsychiatric outcomes; components of these can be modeled by behavioral sensitization in rats. Methods To investigate the role of CYP2D in the brain in methamphetamine-induced behavioral sensitization, rats were pretreated centrally with a CYP2D irreversible inhibitor (or vehicle) 20 h prior to each of 7 daily methamphetamine (0.5 mg/kg subcutaneous) injections. In vivo brain microdialysis was used to assess brain drug and metabolite concentrations, and neurotransmitter release. Results CYP2D inhibitor (versus vehicle) pretreatment enhanced methamphetamine-induced stereotypy response sensitization. CYP2D inhibitor pretreatment increased brain methamphetamine concentrations and decreased the brain p-hydroxylation metabolic ratio. With microdialysis conducted on days 1 and 7, CYP2D inhibitor pretreatment exacerbated stereotypy sensitization and enhanced dopamine and serotonin release in the dorsal striatum. Day 1 brain methamphetamine and amphetamine concentrations correlated with dopamine and serotonin release, which in turn correlated with the stereotypy response slope across sessions (i.e., day 1 through day 7), used as a measure of sensitization. Conclusions CYP2D-mediated methamphetamine metabolism in the brain is sufficient to alter behavioral sensitization, brain drug concentrations, and striatal dopamine and serotonin release. Moreover, day 1 methamphetamine-induced neurotransmitter release may be an important predictor of subsequent behavioral sensitization. This suggests the novel contribution of CYP2D in the brain to methamphetamine-induced behavioral sensitization and suggests that the wide variation in human brain CYP2D6 may contribute to differential methamphetamine responses and chronic effects.

scholarly journals News about the Role of Fluid and Imaging Biomarkers in Neurodegenerative Diseases

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 252
Author(s):  
Jacopo Meldolesi
Keyword(s):  
Neurodegenerative Diseases ◽  
Imaging Techniques ◽  
Imaging Biomarkers ◽  
Positron Emission ◽  
Specific Proteins ◽  
Great Relevance ◽  
The Brain ◽  
Positive Point

Biomarkers are molecules that are variable in their origin, nature, and mechanism of action; they are of great relevance in biology and also in medicine because of their specific connection with a single or several diseases. Biomarkers are of two types, which in some cases are operative with each other. Fluid biomarkers, started around 2000, are generated in fluid from specific proteins/peptides and miRNAs accumulated within two extracellular fluids, either the central spinal fluid or blood plasma. The switch of these proteins/peptides and miRNAs, from free to segregated within extracellular vesicles, has induced certain advantages including higher levels within fluids and lower operative expenses. Imaging biomarkers, started around 2004, are identified in vivo upon their binding by radiolabeled molecules subsequently revealed in the brain by positron emission tomography and/or other imaging techniques. A positive point for the latter approach is the quantitation of results, but expenses are much higher. At present, both types of biomarker are being extensively employed to study Alzheimer’s and other neurodegenerative diseases, investigated from the presymptomatic to mature stages. In conclusion, biomarkers have revolutionized scientific and medical research and practice. Diagnosis, which is often inadequate when based on medical criteria only, has been recently improved by the multiplicity and specificity of biomarkers. Analogous results have been obtained for prognosis. In contrast, improvement of therapy has been limited or fully absent, especially for Alzheimer’s in which progress has been inadequate. An urgent need at hand is therefore the progress of a new drug trial design together with patient management in clinical practice.

The use of siRNA as a pharmacological tool to assess a role for the transcription factor NF-IL6 in the brain under in vitro and in vivo conditions during LPS-induced inflammatory stimulation

2017 ◽  
Vol 28 (6) ◽  
Author(s):  
Jelena Damm ◽  
Joachim Roth ◽  
Rüdiger Gerstberger ◽  
Christoph Rummel
Keyword(s):  
Transcription Factor ◽  
Brain Cells ◽  
Nuclear Factor ◽  
Si Rna ◽  
The Brain ◽  
Deficient Mice ◽  
Transcription Factor Nuclear Factor

AbstractBackground:Studies with NF-IL6-deficient mice indicate that this transcription factor plays a dual role during systemic inflammation with pro- and anti-inflammatory capacities. Here, we aimed to characterize the role of NF-IL6 specifically within the brain.Methods:In this study, we tested the capacity of short interfering (si) RNA to silence the inflammatory transcription factor nuclear factor-interleukin 6 (NF-IL6) in brain cells underResults:In cells of a mixed neuronal and glial primary culture from the ratConclusions:This approach was, thus, not suitable to characterize the role NF-IL6 in the brain

scholarly journals Neuronal spreading and plaque induction of intracellular Aβ and its disruption of Aβ homeostasis

2021 ◽  
Author(s):  
Tomas T. Roos ◽  
Megg G. Garcia ◽  
Isak Martinsson ◽  
Rana Mabrouk ◽  
Bodil Israelsson ◽  
...  
Keyword(s):  
Brain Homogenate ◽  
Fold Increase ◽  
Amyloid Beta Peptide ◽  
Intracellular Accumulation ◽  
Brain Areas ◽  
Cellular Models ◽  
Beta Peptide ◽  
The Brain

AbstractThe amyloid-beta peptide (Aβ) is thought to have prion-like properties promoting its spread throughout the brain in Alzheimer’s disease (AD). However, the cellular mechanism(s) of this spread remains unclear. Here, we show an important role of intracellular Aβ in its prion-like spread. We demonstrate that an intracellular source of Aβ can induce amyloid plaques in vivo via hippocampal injection. We show that hippocampal injection of mouse AD brain homogenate not only induces plaques, but also damages interneurons and affects intracellular Aβ levels in synaptically connected brain areas, paralleling cellular changes seen in AD. Furthermore, in a primary neuron AD model, exposure of picomolar amounts of brain-derived Aβ leads to an apparent redistribution of Aβ from soma to processes and dystrophic neurites. We also observe that such neuritic dystrophies associate with plaque formation in AD-transgenic mice. Finally, using cellular models, we propose a mechanism for how intracellular accumulation of Aβ disturbs homeostatic control of Aβ levels and can contribute to the up to 10,000-fold increase of Aβ in the AD brain. Our data indicate an essential role for intracellular prion-like Aβ and its synaptic spread in the pathogenesis of AD.

ATP-binding cassette transporters and neurodegenerative diseases

2021 ◽  
Author(s):  
Jared S. Katzeff ◽  
Woojin Scott Kim
Keyword(s):  
Neurodegenerative Diseases ◽  
Abc Transporters ◽  
Brain Diseases ◽  
Atp Binding ◽  
Future Directions ◽  
Diverse Range ◽  
The Brain ◽  
Lateral Sclerosis ◽  
Atp Binding Cassette

Abstract ATP-binding cassette (ABC) transporters are one of the largest groups of transporter families in humans. ABC transporters mediate the translocation of a diverse range of substrates across cellular membranes, including amino acids, nucleosides, lipids, sugars and xenobiotics. Neurodegenerative diseases are a group of brain diseases that detrimentally affect neurons and other brain cells and are usually associated with deposits of pathogenic proteins in the brain. Major neurodegenerative diseases include Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. ABC transporters are highly expressed in the brain and have been implicated in a number of pathological processes underlying neurodegenerative diseases. This review outlines the current understanding of the role of ABC transporters in neurodegenerative diseases, focusing on some of the most important pathways, and also suggests future directions for research in this field.

Essential role of oligodendrocytes in the formation and maintenance of central nervous system nodal regions

Development ◽  
2001 ◽  
Vol 128 (23) ◽  
pp. 4881-4890 ◽  
Author(s):  
Carole Mathis ◽  
Natalia Denisenko-Nehrbass ◽  
Jean-Antoine Girault ◽  
Emiliana Borrelli
Keyword(s):  
Na Channels ◽  
Myelinated Axons ◽  
K Channels ◽  
Protein Levels ◽  
Ankyrin G ◽  
Specific Proteins ◽  
Jimpy Mice ◽  
The Brain

The membrane of myelinated axons is divided into functionally distinct domains characterized by the enrichment of specific proteins. The mechanisms responsible for this organization have not been fully identified. To further address the role of oligodendrocytes in the functional segmentation of the axolemma in vivo, the distribution of nodal (Na+ channels, ankyrin G), paranodal (paranodin/contactin-associated-protein) and juxtaparanodal (Kv1.1 K+ channels) axonal markers, was studied in the brain of MBP-TK and jimpy mice. In MBP-TK transgenic mice, oligodendrocyte ablation was selectively induced by FIAU treatment before and during the onset of myelination. In jimpy mice, oligodendrocytes degenerate spontaneously within the first postnatal weeks after the onset of myelination. Interestingly, in MBP-TK mice treated for 1-20 days with FIAU, despite the ablation of more than 95% of oligodendrocytes, the protein levels of all tested nodal markers was unaltered. Nevertheless, these proteins failed to cluster in the nodal regions. By contrast, in jimpy mice, despite a diffused localization of paranodin, the formation of nodal clusters of Na+ channels and ankyrin G was observed. Furthermore, K+ channels clusters were transiently visible, but were in direct contact with nodal markers. These results demonstrate that the organization of functional domains in myelinated axons is oligodendrocyte dependent. They also show that the presence of these cells is a requirement for the maintenance of nodal and paranodal regions.

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