scholarly journals N-terminal phosphorylation of Huntingtin: A molecular switch for regulating Htt aggregation, helical conformation, internalization and nuclear targeting

2018 ◽  
Author(s):  
Sean M. DeGuire ◽  
Francesco. S. Ruggeri ◽  
Mohamed-Bilal Fares ◽  
Anass Chiki ◽  
Urszula Cendrowska ◽  
...  
Keyword(s):  
Membrane Binding ◽  
Serine Phosphorylation ◽  
Helical Conformation ◽  
Nuclear Targeting ◽  
Huntingtin Protein ◽  
Health And Disease ◽  
Bona Fide ◽  
Α Helix ◽  
And Function

AbstractPhosphorylation of exon1 of the Huntingtin protein (Httex1) has been shown to play important roles in regulating the structure, toxicity and cellular properties of N-terminal fragments and the full-length Huntingtin protein. Here, we investigated and compared the effect of bona fide phosphorylation at S13 and/or S16 on the structure, aggregation, membrane binding, and subcellular properties of mutant Httex1-Q18A. We show that serine phosphorylation at either S13 or S16 strongly disrupts the amphipathic α-helix of the N-terminus, inhibits the aggregation of mutant Httex1 and prompts the internalization and nuclear targeting of Httex1 preformed aggregates. In synthetic peptides phosphorylation at S13 and/or S16 strongly disrupted the amphipathic α-helix of the N-terminal 17 residues (Nt17) of Httex1 and Nt17 membrane binding. Our studies on peptides bearing a different combination of phosphorylation sites within Nt17 revealed a novel phosphorylation-dependent switch for regulating the structure of Httex1 involving crosstalk between phosphorylation at T3 and S13 or S16. Together, our results provide novel insights into the role of phosphorylation in regulating Httex1 structure and function in health and disease and underscore the critical importance of identifying enzymes responsible for regulating Htt phosphorylation and their potential as therapeutic targets for the treatment of Huntington’s disease.

scholarly journals Role of Biological Sex in the Cardiovascular-Gut Microbiome Axis

2022 ◽  
Vol 8 ◽  
Author(s):  
Shuangyue Li ◽  
Georgios Kararigas
Keyword(s):  
Gut Microbiota ◽  
Gut Microbiome ◽  
Microbial Composition ◽  
Biological Sex ◽  
Technological Advances ◽  
Host Health ◽  
Health And Disease ◽  
And Function ◽  
Insight Into

There has been a recent, unprecedented interest in the role of gut microbiota in host health and disease. Technological advances have dramatically expanded our knowledge of the gut microbiome. Increasing evidence has indicated a strong link between gut microbiota and the development of cardiovascular diseases (CVD). In the present article, we discuss the contribution of gut microbiota in the development and progression of CVD. We further discuss how the gut microbiome may differ between the sexes and how it may be influenced by sex hormones. We put forward that regulation of microbial composition and function by sex might lead to sex-biased disease susceptibility, thereby offering a mechanistic insight into sex differences in CVD. A better understanding of this could identify novel targets, ultimately contributing to the development of innovative preventive, diagnostic and therapeutic strategies for men and women.

scholarly journals Chromatin Enrichment for Proteomics in Plants (ChEP-P) Implicates the Histone Reader ALFIN-LIKE 6 in Jasmonate Signalling

2021 ◽  
Author(s):  
Isabel Cristina Vélez-Bermúdez ◽  
Wolfgang Schmidt
Keyword(s):  
Histone Variants ◽  
Homeodomain Protein ◽  
Chromatin Dynamics ◽  
Histone 3 ◽  
Plant Homeodomain ◽  
Associated Proteins ◽  
Bona Fide ◽  
Covalent Modifications ◽  
And Function

Abstract BackgroundCovalent modifications of core histonesgoverndownstream DNA-templated processes such as transcription by altering chromatin structure and function. Previously, we reported that the plant homeodomain protein ALFIN-LIKE6 (AL6), a bona fide histone reader that preferentially binds trimethylated lysin 4 on histone 3 (H3K4me3), is critical for recalibration of cellular phosphate (Pi) homeostasis and root hair elongation under Pi-deficient conditions. ResultsHere, we demonstrate that AL6 is also involved in the response of Arabidopsis seedlings to jasmonic acid (JA) during skotomorphogenesis, possibly by modulating chromatin dynamics that affect the transcriptional regulation of JA-responsivegenes. Dark-grown al6 seedlings showed a compromised reduction in hypocotyl elongation upon exogenously supplied JA, a response that was calibrated by the availability of Pi in the growth medium. A comparison of protein profiles between wild-type and al6 mutant seedlings using a quantitative Chromatin Enrichment for Proteomics (ChEP) approach,that we modified for plant tissue and designated ChEP-P (ChEP in Plants), yielded a comprehensive suite of chromatin-associated proteins and candidates that may be causative for the mutant phenotype. ConclusionsAltered abundance of proteins involved in chromatin organization in al6 seedlings suggests a role of AL6 in coordinating the deposition of histone variants upon perception of internal or environmental stimuli. Our study shows that ChEP-P is well suited to gain holistic insights into chromatin-related processes in plants. Data are available via ProteomeXchange with identifier PXD026541.

scholarly journals Sex Differences and the Influence of Sex Hormones on Cognition through Adulthood and the Aging Process

2018 ◽  
Vol 8 (9) ◽  
pp. 163 ◽  
Author(s):  
Caroline Gurvich ◽  
Kate Hoy ◽  
Natalie Thomas ◽  
Jayashri Kulkarni
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Sex Differences ◽  
Cognitive Functioning ◽  
Sex Hormones ◽  
Reproductive Function ◽  
Health And Disease ◽  
And Function ◽  
The Brain

Hormones of the hypothalamic-pituitary-gonadal (HPG) axis that regulate reproductive function have multiple effects on the development, maintenance and function of the brain. Sex differences in cognitive functioning have been reported in both health and disease, which may be partly attributed to sex hormones. The aim of the current paper was to provide a theoretical review of how sex hormones influence cognitive functioning across the lifespan as well as provide an overview of the literature on sex differences and the role of sex hormones in cognitive decline, specifically in relation to Alzheimer’s disease (AD). A summary of current hormone and sex-based interventions for enhancing cognitive functioning and/or reducing the risk of Alzheimer’s disease is also provided.

scholarly journals Novel Insights From Human Studies on the Role of High-Density Lipoprotein in Mortality and Noncardiovascular Disease

2020 ◽  
Author(s):  
Christian M. Madsen ◽  
Anette Varbo ◽  
Børge G. Nordestgaard
Keyword(s):  
Cardiovascular Disease ◽  
High Density Lipoprotein ◽  
Therapeutic Potential ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
High Density ◽  
Cancer Type ◽  
Health And Disease ◽  
And Function

The vast majority of research about HDL (high-density lipoprotein) has for decades revolved around the possible role of HDL in atherosclerosis and its therapeutic potential within cardiovascular disease prevention; however, failures with therapies aimed at increasing HDL cholesterol has left questions as to what the role and function of HDL in human health and disease is. Recent observational studies have further shown that extreme high HDL cholesterol is associated with high mortality leading to speculations that HDL could in some instances be harmful. In addition, evidence from observational, and to a lesser extent genetic, studies has emerged indicating that HDL might be associated with the development of other major noncardiovascular diseases, such as infectious disease, autoimmune disease, cancer, type 2 diabetes, kidney disease, and lung disease. In this review, we discuss (1) the association between extreme high HDL cholesterol and mortality and (2) the emerging human evidence linking HDL to several major diseases outside the realm of cardiovascular disease.

scholarly journals Nbr1 Is a Novel Inhibitor of Ligand-Mediated Receptor Tyrosine Kinase Degradation

2010 ◽  
Vol 30 (24) ◽  
pp. 5672-5685 ◽  
Author(s):  
Faraz K. Mardakheh ◽  
Giulio Auciello ◽  
Tim R. Dafforn ◽  
Joshua Z. Rappoport ◽  
John K. Heath
Keyword(s):  
Tyrosine Kinases ◽  
Protein Localization ◽  
Negative Regulator ◽  
Receptor Internalization ◽  
C Terminus ◽  
Late Endosomes ◽  
Exact Function ◽  
Α Helix ◽  
And Function

ABSTRACT Neighbor of BRCA1 (Nbr1) is a highly conserved multidomain scaffold protein with proposed roles in endocytic trafficking and selective autophagy. However, the exact function of Nbr1 in these contexts has not been studied in detail. Here we investigated the role of Nbr1 in the trafficking of receptor tyrosine kinases (RTKs). We report that ectopic Nbr1 expression inhibits the ligand-mediated lysosomal degradation of RTKs, and this is probably done via the inhibition of receptor internalization. Conversely, the depletion of endogenous NBR1 enhances RTK degradation. Analyses of truncation mutations demonstrated that the C terminus of Nbr1 is essential but not sufficient for this activity. Moreover, the C terminus of Nbr1 is essential but not sufficient for the localization of the protein to late endosomes. We demonstrate that the C terminus of Nbr1 contains a novel membrane-interacting amphipathic α-helix, which is essential for the late endocytic localization of the protein but not for its effect on RTK degradation. Finally, autophagic and late endocytic localizations of Nbr1 are independent of one another, suggesting that the roles of Nbr1 in each context might be distinct. Our results define Nbr1 as a negative regulator of ligand-mediated RTK degradation and reveal the interplay between its various regions for protein localization and function.

scholarly journals Serine protease inhibitors and human wellbeing interplay: new insights for old friends

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7224 ◽  
Author(s):  
Héla Mkaouar ◽  
Nizar Akermi ◽  
Aicha Kriaa ◽  
Anne-Laure Abraham ◽  
Amin Jablaoui ◽  
...  
Keyword(s):  
Serine Protease ◽  
Protease Inhibitors ◽  
Structural Data ◽  
Ecological Niches ◽  
Serine Protease Inhibitors ◽  
New Therapeutic Approaches ◽  
Physiological Processes ◽  
Health And Disease ◽  
And Function

Serine Protease Inhibitors (Serpins) control tightly regulated physiological processes and their dysfunction is associated to various diseases. Thus, increasing interest is given to these proteins as new therapeutic targets. Several studies provided functional and structural data about human serpins. By comparison, only little knowledge regarding bacterial serpins exists. Through the emergence of metagenomic studies, many bacterial serpins were identified from numerous ecological niches including the human gut microbiota. The origin, distribution and function of these proteins remain to be established. In this report, we shed light on the key role of human and bacterial serpins in health and disease. Moreover, we analyze their function, phylogeny and ecological distribution. This review highlights the potential use of bacterial serpins to set out new therapeutic approaches.

Autophagy in health and disease: focus on the cardiovascular system

2017 ◽  
Vol 61 (6) ◽  
pp. 721-732 ◽  
Author(s):  
Jeanne Mialet-Perez ◽  
Cécile Vindis
Keyword(s):  
Heart Failure ◽  
Cardiovascular System ◽  
Crucial Role ◽  
Current Knowledge ◽  
Cardiovascular Disorders ◽  
Health And Disease ◽  
And Function ◽  
Autophagy Activity ◽  
Disease Focus

Autophagy is a highly conserved mechanism of lysosome-mediated protein and organelle degradation that plays a crucial role in maintaining cellular homeostasis. In the last few years, specific functions for autophagy have been identified in many tissues and organs. In the cardiovascular system, autophagy appears to be essential to heart and vessel homeostasis and function; however defective or excessive autophagy activity seems to contribute to major cardiovascular disorders including heart failure (HF) or atherosclerosis. Here, we review the current knowledge on the role of cardiovascular autophagy in physiological and pathophysiological conditions.

scholarly journals Role of Choline in Ocular Diseases

2021 ◽  
Vol 22 (9) ◽  
pp. 4733
Author(s):  
Jin-Sun Hwang ◽  
Young-Joo Shin
Keyword(s):  
Parasympathetic Nervous System ◽  
Retinal Hemorrhage ◽  
Ocular Diseases ◽  
Choline Deficiency ◽  
Eye Health ◽  
Development And Differentiation ◽  
Health And Disease ◽  
The Stability ◽  
And Function

Choline is essential for maintaining the structure and function of cells in humans. Choline plays an important role in eye health and disease. It is a precursor of acetylcholine, a neurotransmitter of the parasympathetic nervous system, and it is involved in the production and secretion of tears by the lacrimal glands. It also contributes to the stability of the cells and tears on the ocular surface and is involved in retinal development and differentiation. Choline deficiency is associated with retinal hemorrhage, glaucoma, and dry eye syndrome. Choline supplementation may be effective for treating these diseases.

scholarly journals Intestinal microbiota during early life – impact on health and disease

2014 ◽  
Vol 73 (4) ◽  
pp. 457-469 ◽  
Author(s):  
Lotta Nylund ◽  
Reetta Satokari ◽  
Seppo Salminen ◽  
Willem M. de Vos
Keyword(s):  
Intestinal Microbiota ◽  
Early Life ◽  
Later Life ◽  
Related Factors ◽  
Life Impact ◽  
Health And Disease ◽  
And Function ◽  
The Impact

In the first years after birth, the intestinal microbiota develops rapidly both in diversity and complexity while being relatively stable in healthy adults. Different life-style-related factors as well as medical practices have an influence on the early-life intestinal colonisation. We address the impact of some of these factors on the consecutive microbiota development and later health. An overview is presented of the microbial colonisation steps and the role of the host in that process. Moreover, new early biomarkers are discussed with examples that include the association of microbiota and atopic diseases, the correlation of colic and early development and the impact of the use of antibiotics in early life. Our understanding of the development and function of the intestinal microbiota is constantly improving but the long-term influence of early-life microbiota on later life health deserves careful clinical studies.

scholarly journals BIOMARKERS OF CARDIAC FIBROSIS IN ARTERIAL HYPERTENSION

2020 ◽  
Vol 47 (4) ◽  
Author(s):  
N. Ya. Dotsenko ◽  
L. V. Gerasimenko ◽  
S. S. Boev ◽  
I. A. Shekhunova ◽  
A. V. Molodan ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Arterial Hypertension ◽  
Myocardial Fibrosis ◽  
Cardiac Fibrosis ◽  
Structure And Function ◽  
Myocardial Remodeling ◽  
Review Of The Literature ◽  
Health And Disease ◽  
And Function

Abstract The article presents a review of the literature on the role of myocardial fibrosis in the development of myocardial remodeling in patients with arterial hypertension. Information about the state of the structure and function of the extracellular matrix in health and disease is generalized. The characteristics of myocardial fibrosis biomarkers detection in the circulating blood are reflected. Keywords: arterial hypertension, myocardial fibrosis, extracellular matrix, collagen, biomarkers.

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