Treponema, Iron and Neurodegeneration

Spirochetes are suspected to be linked to the genesis of neurological diseases, including neurosyphillis or neurodegeneration (ND). Impaired iron homeostasis has been implicated in loss of function in several enzymes requiring iron as a cofactor, formation of toxic oxidative species, inflammation and elevated production of beta-amyloid proteins. This review proposes to discuss the link that may exist between the involvement of Treponema spp. in the genesis or worsening of ND, and iron dyshomeostasis. Proteins secreted by Treponema can act directly on iron metabolism, with hemin binding ability (HbpA and HbpB) and iron reductase able to reduce the central ferric iron of hemin, iron-containing proteins (rubredoxin, neelaredoxin, desulfoferrodoxin metalloproteins, bacterioferritins etc). Treponema can also interact with cellular compounds, especially plasma proteins involved in iron metabolism, contributing to the virulence of the syphilis spirochetes (e.g. treponemal motility and survival). Fibronectin, transferrin and lactoferrin were also shown to be receptors for treponemal adherence to host cells and extracellular matrix. Association between Treponema and iron binding proteins results in iron accumulation and sequestration by Treponema from host macromolecules during systemic and mucosal infections.

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Cockayne syndrome B protein acts as an ATP-dependent processivity factor that helps RNA polymerase II overcome nucleosome barriers

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2013379117 ◽

2020 ◽

Vol 117 (41) ◽

pp. 25486-25493 ◽

Cited By ~ 1

Author(s):

Jun Xu ◽

Wei Wang ◽

Liang Xu ◽

Jia-Yu Chen ◽

Jenny Chong ◽

...

Keyword(s):

Rna Polymerase Ii ◽

Neurological Diseases ◽

Transcription Elongation ◽

Cockayne Syndrome ◽

Stable Complex ◽

Loss Of Function ◽

Pol Ii ◽

Chromatin Remodelers ◽

Processivity Factor

While loss-of-function mutations in Cockayne syndrome group B protein (CSB) cause neurological diseases, this unique member of the SWI2/SNF2 family of chromatin remodelers has been broadly implicated in transcription elongation and transcription-coupled DNA damage repair, yet its mechanism remains largely elusive. Here, we use a reconstituted in vitro transcription system with purified polymerase II (Pol II) and Rad26, a yeast ortholog of CSB, to study the role of CSB in transcription elongation through nucleosome barriers. We show that CSB forms a stable complex with Pol II and acts as an ATP-dependent processivity factor that helps Pol II across a nucleosome barrier. This noncanonical mechanism is distinct from the canonical modes of chromatin remodelers that directly engage and remodel nucleosomes or transcription elongation factors that facilitate Pol II nucleosome bypass without hydrolyzing ATP. We propose a model where CSB facilitates gene expression by helping Pol II bypass chromatin obstacles while maintaining their structures.

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The Interplay between Drivers of Erythropoiesis and Iron Homeostasis in Rare Hereditary Anemias: Tipping the Balance

International Journal of Molecular Sciences ◽

10.3390/ijms22042204 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2204

Author(s):

Simon Grootendorst ◽

Jonathan de Wilde ◽

Birgit van Dooijeweert ◽

Annelies van Vuren ◽

Wouter van Solinge ◽

...

Keyword(s):

Iron Overload ◽

Iron Metabolism ◽

Iron Homeostasis ◽

Significant Problem ◽

Blood Transfusions ◽

Intrinsic Defects ◽

Chronic Anemia ◽

Erythroid Development ◽

Disease Specific

Rare hereditary anemias (RHA) represent a group of disorders characterized by either impaired production of erythrocytes or decreased survival (i.e., hemolysis). In RHA, the regulation of iron metabolism and erythropoiesis is often disturbed, leading to iron overload or worsening of chronic anemia due to unavailability of iron for erythropoiesis. Whereas iron overload generally is a well-recognized complication in patients requiring regular blood transfusions, it is also a significant problem in a large proportion of patients with RHA that are not transfusion dependent. This indicates that RHA share disease-specific defects in erythroid development that are linked to intrinsic defects in iron metabolism. In this review, we discuss the key regulators involved in the interplay between iron and erythropoiesis and their importance in the spectrum of RHA.

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Codon harmonization reduces amino acid misincorporation in bacterially expressed P. falciparum proteins and improves their immunogenicity

AMB Express ◽

10.1186/s13568-019-0890-6 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Neeraja Punde ◽

Jennifer Kooken ◽

Dagmar Leary ◽

Patricia M. Legler ◽

Evelina Angov

Keyword(s):

Protein Structure ◽

Amino Acid ◽

Codon Usage ◽

Dna Sequences ◽

Structural Integrity ◽

Host Cells ◽

Loss Of Function ◽

Species Specific ◽

And Function ◽

The Impact

Abstract Codon usage frequency influences protein structure and function. The frequency with which codons are used potentially impacts primary, secondary and tertiary protein structure. Poor expression, loss of function, insolubility, or truncation can result from species-specific differences in codon usage. “Codon harmonization” more closely aligns native codon usage frequencies with those of the expression host particularly within putative inter-domain segments where slower rates of translation may play a role in protein folding. Heterologous expression of Plasmodium falciparum genes in Escherichia coli has been a challenge due to their AT-rich codon bias and the highly repetitive DNA sequences. Here, codon harmonization was applied to the malarial antigen, CelTOS (Cell-traversal protein for ookinetes and sporozoites). CelTOS is a highly conserved P. falciparum protein involved in cellular traversal through mosquito and vertebrate host cells. It reversibly refolds after thermal denaturation making it a desirable malarial vaccine candidate. Protein expressed in E. coli from a codon harmonized sequence of P. falciparum CelTOS (CH-PfCelTOS) was compared with protein expressed from the native codon sequence (N-PfCelTOS) to assess the impact of codon usage on protein expression levels, solubility, yield, stability, structural integrity, recognition with CelTOS-specific mAbs and immunogenicity in mice. While the translated proteins were expected to be identical, the translated products produced from the codon-harmonized sequence differed in helical content and showed a smaller distribution of polypeptides in mass spectra indicating lower heterogeneity of the codon harmonized version and fewer amino acid misincorporations. Substitutions of hydrophobic-to-hydrophobic amino acid were observed more commonly than any other. CH-PfCelTOS induced significantly higher antibody levels compared with N-PfCelTOS; however, no significant differences in either IFN-γ or IL-4 cellular responses were detected between the two antigens.

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The liver in regulation of iron homeostasis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00004.2017 ◽

2017 ◽

Vol 313 (3) ◽

pp. G157-G165 ◽

Cited By ~ 30

Author(s):

Gautam Rishi ◽

V. Nathan Subramaniam

Keyword(s):

Plasma Proteins ◽

Iron Homeostasis ◽

Vital Role ◽

Regulatory Function ◽

Hepatic Iron ◽

Storage Site ◽

Molecular Processes ◽

Body Iron ◽

Functionally Diverse ◽

And Storage

The liver is one of the largest and most functionally diverse organs in the human body. In addition to roles in detoxification of xenobiotics, digestion, synthesis of important plasma proteins, gluconeogenesis, lipid metabolism, and storage, the liver also plays a significant role in iron homeostasis. Apart from being the storage site for excess body iron, it also plays a vital role in regulating the amount of iron released into the blood by enterocytes and macrophages. Since iron is essential for many important physiological and molecular processes, it increases the importance of liver in the proper functioning of the body’s metabolism. This hepatic iron-regulatory function can be attributed to the expression of many liver-specific or liver-enriched proteins, all of which play an important role in the regulation of iron homeostasis. This review focuses on these proteins and their known roles in the regulation of body iron metabolism.

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ChemInform Abstract: Brain Iron Metabolism and Its Perturbation in Neurological Diseases

ChemInform ◽

10.1002/chin.201132264 ◽

2011 ◽

Vol 42 (32) ◽

pp. no-no ◽

Cited By ~ 1

Author(s):

Robert R. Crichton ◽

David T. Dexter ◽

Roberta J. Ward

Keyword(s):

Iron Metabolism ◽

Neurological Diseases ◽

Brain Iron ◽

Brain Iron Metabolism

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The disorder of the iron metabolism as a possible mechanism for the development of neurodegeneration after new coronavirus infection of SARS-CoV-2

Russian Military Medical Academy Reports ◽

10.17816/rmmar83609 ◽

2021 ◽

Vol 40 (4) ◽

pp. 13-24

Author(s):

Igor V. Litvinenko ◽

Igor V. Krasakov

Keyword(s):

Nervous System ◽

Neurodegenerative Diseases ◽

Iron Metabolism ◽

Iron Homeostasis ◽

Molecular Mechanisms ◽

Brain Structures ◽

Pathological Process ◽

Parkinsons Disease ◽

Neurodegenerative Process ◽

Coronavirus Infection

The involvement of the nervous system in the pathological process that occurs when COVID-19 is infected is becoming more and more obvious. The question of the possibility of the debut or progression of the already developed Parkinsonism syndrome in patients who have undergone COVID-19 is regularly raised. A large number of hypotheses are put forward to explain this relationship. It is assumed that a violation of iron metabolism in the brain may underlie the development and progression of neurodegenerative diseases, including after the new coronavirus infection SARS-CoV-2. The analysis of stu dies on the possible influence of iron metabolism disorders on the occurrence and mechanism of development of neurodegenerative diseases after infection with SARS-CoV-2 has been carried out. The processes of physiological maintenance of iron homeostasis, as well as the influence of physiological aging on the accumulation of iron in the central nervous system are described. The relationship between hyperferritinemia occurring in COVID-19 and ferroptosis as the basis of the neurodegenerative process in Parkinsons disease and Alzheimers disease is discussed. The main molecular mechanisms involved in ferroptosis are described. Examples of involvement of metal homeostasis disorders in the process of altering the structure of -synuclein, synthesis of -amyloid, hyperphosphorylated tau- protein are given. The causes of excessive iron accumulation in certain brain structures are discussed. The question of the possibility of using the assessment of changes in iron metabolism as a new biomarker of the progression of Parkinsons disease is analyzed. (1 figure, bibliography: 62 refs)

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A streamlined method for transposon mutagenesis ofRickettsia parkeriyields numerous mutations that impact infection

10.1101/277160 ◽

2018 ◽

Author(s):

Rebecca L. Lamason ◽

Natasha M. Kafai ◽

Matthew D. Welch

Keyword(s):

Host Cell ◽

Virulence Factors ◽

Vascular Endothelial Cells ◽

Spotted Fever ◽

Transposon Mutagenesis ◽

Host Cells ◽

Spotted Fever Group ◽

Loss Of Function ◽

Rickettsia Parkeri ◽

Obligate Intracellular

AbstractThe rickettsiae are obligate intracellular alphaproteobacteria that exhibit a complex infectious life cycle in both arthropod and mammalian hosts. As obligate intracellular bacteria,Rickettsiaare highly adapted to living inside a variety of host cells, including vascular endothelial cells during mammalian infection. Although it is assumed that the rickettsiae produce numerous virulence factors that usurp or disrupt various host cell pathways, they have been challenging to genetically manipulate to identify the key bacterial factors that contribute to infection. Motivated to overcome this challenge, we sought to expand the repertoire of available rickettsial loss-of-function mutants, using an improvedmariner-based transposon mutagenesis scheme. Here, we present the isolation of over 100 transposon mutants in the spotted fever group speciesRickettsia parkeri. These mutants targeted genes implicated in a variety of pathways, including bacterial replication and metabolism, hypothetical proteins, the type IV secretion system, as well as factors with previously established roles in host cell interactions and pathogenesis. Given the need to identify critical virulence factors, forward genetic screens such as this will provide an excellent platform to more directly investigate rickettsial biology and pathogenesis.

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Insights Into the Role of CSF1R in the Central Nervous System and Neurological Disorders

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.789834 ◽

2021 ◽

Vol 13 ◽

Author(s):

Banglian Hu ◽

Shengshun Duan ◽

Ziwei Wang ◽

Xin Li ◽

Yuhang Zhou ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Neurological Disorders ◽

Neurological Diseases ◽

Colony Stimulating Factor ◽

Loss Of Function ◽

Axonal Spheroids ◽

The Central Nervous System ◽

Stimulating Factor

The colony-stimulating factor 1 receptor (CSF1R) is a key tyrosine kinase transmembrane receptor modulating microglial homeostasis, neurogenesis, and neuronal survival in the central nervous system (CNS). CSF1R, which can be proteolytically cleaved into a soluble ectodomain and an intracellular protein fragment, supports the survival of myeloid cells upon activation by two ligands, colony stimulating factor 1 and interleukin 34. CSF1R loss-of-function mutations are the major cause of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and its dysfunction has also been implicated in other neurodegenerative disorders including Alzheimer’s disease (AD). Here, we review the physiological functions of CSF1R in the CNS and its pathological effects in neurological disorders including ALSP, AD, frontotemporal dementia and multiple sclerosis. Understanding the pathophysiology of CSF1R is critical for developing targeted therapies for related neurological diseases.

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Cerebrospinal fluid transferrin levels are reduced in patients with early multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458514530020 ◽

2014 ◽

Vol 20 (12) ◽

pp. 1569-1577 ◽

Cited By ~ 8

Author(s):

M Khalil ◽

B Riedlbauer ◽

C Langkammer ◽

C Enzinger ◽

S Ropele ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Iron Metabolism ◽

Iron Homeostasis ◽

Biochemical Study ◽

Iron Deposition ◽

Lesion Load ◽

Transporter Protein ◽

In Cis ◽

The Brain

Background: Previous magnetic resonance imaging (MRI) studies have demonstrated increased iron deposition in the basal ganglia of multiple sclerosis (MS) patients. However, it is not clear whether these alterations are associated with changes of iron metabolism in body fluids. Objectives: The purpose of this study was to investigate if iron metabolism markers in cerebrospinal fluid (CSF) and serum of clinically isolated syndrome (CIS) and MS patients differ from controls and how they relate to clinical and imaging parameters. Methods: We analysed serum ferritin, transferrin and soluble transferrin-receptor and CSF ferritin and transferrin by nephelometry in non-anaemic CIS ( n=60) or early MS ( n=14) patients and 68 controls. In CIS/MS we additionally assessed the T2 lesion load. Results: CSF transferrin was significantly decreased in CIS/MS compared to controls ( p<0.001), while no significant differences were seen in serum. Higher CSF transferrin levels correlated with lower physical disability scores ( r= −0.3, p<0.05). CSF transferrin levels did not correlate with other clinical data and the T2 lesion load. Conclusion: Our biochemical study provides evidence that altered iron homeostasis within the brain occurs in the very early phases of the disease, and suggests that the transporter protein transferrin may play a role in the increased iron deposition known to occur in the brain of MS patients.

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Acute invariant NKT cell activation triggers an immune response that drives prominent changes in iron homeostasis

Scientific Reports ◽

10.1038/s41598-020-78037-3 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Hua Huang ◽

Vanessa Zuzarte-Luis ◽

Gabriela Fragoso ◽

Annie Calvé ◽

Tuan Anh Hoang ◽

...

Keyword(s):

Cell Proliferation ◽

Iron Metabolism ◽

Cell Activation ◽

Iron Homeostasis ◽

Immune Cell ◽

Second Phase ◽

Inkt Cells ◽

Strong Suppression ◽

Cellular Processes ◽

Smad Signaling Pathway

AbstractIron homeostasis is an essential biological process that ensures the tissue distribution of iron for various cellular processes. As the major producer of hepcidin, the liver is central to the regulation of iron metabolism. The liver is also home to many immune cells, which upon activation may greatly impact iron metabolism. Here, we focus on the role of invariant natural killer T (iNKT) cells, a subset of T lymphocytes that, in mice, is most abundant in the liver. Activation of iNKT cells with the prototypical glycosphingolipid antigen, α-galactosylceramide, resulted in immune cell proliferation and biphasic changes in iron metabolism. This involved an early phase characterized by hypoferremia, hepcidin induction and ferroportin suppression, and a second phase associated with strong suppression of hepcidin despite elevated levels of circulating and tissue iron. We further show that these changes in iron metabolism are fully dependent on iNKT cell activation. Finally, we demonstrate that the biphasic regulation of hepcidin is independent of NK and Kupffer cells, and is initially driven by the STAT3 inflammatory pathway, whereas the second phase is regulated by repression of the BMP/SMAD signaling pathway. These findings indicate that iNKT activation and the resulting cell proliferation influence iron homeostasis.

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