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Huntingtin associated Protein

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https://www.readbyqxmd.com/read/29765031/comprehensive-epigenetic-landscape-of-rheumatoid-arthritis-fibroblast-like-synoviocytes
#1
Rizi Ai, Teresina Laragione, Deepa Hammaker, David L Boyle, Andre Wildberg, Keisuke Maeshima, Emanuele Palescandolo, Vinod Krishna, David Pocalyko, John W Whitaker, Yuchen Bai, Sunil Nagpal, Kurtis E Bachman, Richard I Ainsworth, Mengchi Wang, Bo Ding, Percio S Gulko, Wei Wang, Gary S Firestein
Epigenetics contributes to the pathogenesis of immune-mediated diseases like rheumatoid arthritis (RA). Here we show the first comprehensive epigenomic characterization of RA fibroblast-like synoviocytes (FLS), including histone modifications (H3K27ac, H3K4me1, H3K4me3, H3K36me3, H3K27me3, and H3K9me3), open chromatin, RNA expression and whole-genome DNA methylation. To address complex multidimensional relationship and reveal epigenetic regulation of RA, we perform integrative analyses using a novel unbiased method to identify genomic regions with similar profiles...
May 15, 2018: Nature Communications
https://www.readbyqxmd.com/read/29764935/the-disorderly-conduct-of-hsc70-and-its-interaction-with-the-alzheimer-s-related-tau-protein
#2
Isabelle R Taylor, Atta Ahmad, Taia Wu, Bryce A Nordhues, Anup Bhullar, Jason E Gestwicki, Erik R P Zuiderweg
Hsp70 chaperones bind to various protein substrates for folding, trafficking, and degradation. Considerable structural information is available about how prokaryotic Hsp70 (DnaK) binds substrates, but less is known about mammalian Hsp70s, of which there are 13 isoforms encoded in the human genome. Here, we report the interaction between the human Hsp70 isoform heat shock cognate 71 KDa protein (Hsc70 or HSPA8) and peptides derived from the microtubule-associated protein tau, which is linked to Alzheimer's disease...
May 15, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29754825/structure-of-human-nata-and-its-regulation-by-the-huntingtin-interacting-protein-hypk
#3
Leah Gottlieb, Ronen Marmorstein
Co-translational N-terminal protein acetylation regulates many protein functions including degradation, folding, interprotein interactions, and targeting. Human NatA (hNatA), one of six conserved metazoan N-terminal acetyltransferases, contains Naa10 catalytic and Naa15 auxiliary subunits, and associates with the intrinsically disordered Huntingtin yeast two-hybrid protein K (HYPK). We report on the crystal structures of hNatA and hNatA/HYPK, and associated biochemical and enzymatic analyses. We demonstrate that hNatA contains unique features: a stabilizing inositol hexaphosphate (IP6 ) molecule and a metazoan-specific Naa15 domain that mediates high-affinity HYPK binding...
April 23, 2018: Structure
https://www.readbyqxmd.com/read/29743513/sphingosine-kinase-1-associated-autophagy-differs-between-neurons-and-astrocytes
#4
Jose F Moruno-Manchon, Ndidi-Ese Uzor, Chandrashekar R Ambati, Vivekananda Shetty, Nagireddy Putluri, Chinnaswamy Jagannath, Louise D McCullough, Andrey S Tsvetkov
Autophagy is a degradative pathway for removing aggregated proteins, damaged organelles, and parasites. Evidence indicates that autophagic pathways differ between cell types. In neurons, autophagy plays a homeostatic role, compared to a survival mechanism employed by starving non-neuronal cells. We investigated if sphingosine kinase 1 (SK1)-associated autophagy differs between two symbiotic brain cell types-neurons and astrocytes. SK1 synthesizes sphingosine-1-phosphate, which regulates autophagy in non-neuronal cells and in neurons...
May 9, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29738460/patient-derived-ipscs-and-ins-shedding-new-light-on-the-cellular-etiology-of-neurodegenerative-diseases
#5
Bor Luen Tang
Induced pluripotent stem cells (iPSCs) and induced neuronal (iN) cells are very much touted in terms of their potential promises in therapeutics. However, from a more fundamental perspective, iPSCs and iNs are invaluable tools for the postnatal generation of specific diseased cell types from patients, which may offer insights into disease etiology that are otherwise unobtainable with available animal or human proxies. There are two good recent examples of such important insights with diseased neurons derived via either the iPSC or iN approaches...
May 8, 2018: Cells
https://www.readbyqxmd.com/read/29698489/altered-distribution-of-atg9a-and-accumulation-of-axonal-aggregates-in-neurons-from-a-mouse-model-of-ap-4-deficiency-syndrome
#6
Raffaella De Pace, Miguel Skirzewski, Markus Damme, Rafael Mattera, Jeffrey Mercurio, Arianne M Foster, Loreto Cuitino, Michal Jarnik, Victoria Hoffmann, H Douglas Morris, Tae-Un Han, Grazia M S Mancini, Andrés Buonanno, Juan S Bonifacino
The hereditary spastic paraplegias (HSP) are a clinically and genetically heterogeneous group of disorders characterized by progressive lower limb spasticity. Mutations in subunits of the heterotetrameric (ε-β4-μ4-σ4) adaptor protein 4 (AP-4) complex cause an autosomal recessive form of complicated HSP referred to as "AP-4 deficiency syndrome". In addition to lower limb spasticity, this syndrome features intellectual disability, microcephaly, seizures, thin corpus callosum and upper limb spasticity...
April 26, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29609019/designing-aptamers-which-respond-to-intracellular-oxidative-stress-and-inhibit-aggregation-of-mutant-huntingtin
#7
Kinjal A Patel, Thulasi Kolluri, Swati Jain, Ipsita Roy
Targeted expression of a therapeutic agent is a major bottleneck in designing a drug delivery system. Protein aggregation and elevated oxidative stress are associated with the onset of many neurodegenerative disorders, including Huntington's disease (HD). An oxidative stress-inducible promoter, i.e. Thioredoxin 2, was employed to design a sensor for protein aggregation. RNA aptamers specific for mutant huntingtin were expressed only in cells where aggregation of mutant huntingtin occurred. A nine-fold increase in RNA expression was seen when aptamer sequences were cloned under the Trx2 promoter...
March 30, 2018: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/29578503/monitoring-cell-to-cell-transmission-of-prion-like-protein-aggregates-in-drosophila-melanogaster
#8
Kirby M Donnelly, Margaret M P Pearce
Protein aggregation is a central feature of most neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Protein aggregates are closely associated with neuropathology in these diseases, although the exact mechanism by which aberrant protein aggregation disrupts normal cellular homeostasis is not known. Emerging data provide strong support for the hypothesis that pathogenic aggregates in AD, PD, HD, and ALS have many similarities to prions, which are protein-only infectious agents responsible for the transmissible spongiform encephalopathies...
March 12, 2018: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29530757/neuromuscular-synapse-degeneration-without-muscle-function-loss-in-the-diaphragm-of-a-murine-model-for-huntington-s-disease
#9
Priscila A C Valadão, Matheus P S M Gomes, Bárbara C Aragão, Hermann A Rodrigues, Jéssica N Andrade, Rubens Garcias, Julliane V Joviano-Santos, Murilo A Luiz, Wallace L Camargo, Lígia A Naves, Christopher Kushmerick, Walter L G Cavalcante, Márcia Gallacci, Itamar C G de Jesus, Silvia Guatimosim, Cristina Guatimosim
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterized by chorea, incoordination and psychiatric and behavioral symptoms. The leading cause of death in HD patients is aspiration pneumonia, associated with respiratory dysfunction, decreased respiratory muscle strength and dysphagia. Although most of the motor symptoms are derived from alterations in the central nervous system, some might be associated with changes in the components of motor units (MU). To explore this hypothesis, we evaluated morphofunctional aspects of the diaphragm muscle in a mouse model for HD (BACHD)...
June 2018: Neurochemistry International
https://www.readbyqxmd.com/read/29503201/translation-of-microrna-based-huntingtin-lowering-therapies-from-preclinical-studies-to-the-clinic
#10
REVIEW
Jana Miniarikova, Melvin M Evers, Pavlina Konstantinova
The single mutation underlying the fatal neuropathology of Huntington's disease (HD) is a CAG triplet expansion in exon 1 of the huntingtin (HTT) gene, which gives rise to a toxic mutant HTT protein. There have been a number of not yet successful therapeutic advances in the treatment of HD. The current excitement in the HD field is due to the recent development of therapies targeting the culprit of HD either at the DNA or RNA level to reduce the overall mutant HTT protein. In this review, we briefly describe short-term and long-term HTT-lowering strategies targeting HTT transcripts...
April 4, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29466333/the-cryo-electron-microscopy-structure-of-huntingtin
#11
Qiang Guo, Bin Huang, Jingdong Cheng, Manuel Seefelder, Tatjana Engler, Günter Pfeifer, Patrick Oeckl, Markus Otto, Franziska Moser, Melanie Maurer, Alexander Pautsch, Wolfgang Baumeister, Rubén Fernández-Busnadiego, Stefan Kochanek
Huntingtin (HTT) is a large (348 kDa) protein that is essential for embryonic development and is involved in diverse cellular activities such as vesicular transport, endocytosis, autophagy and the regulation of transcription. Although an integrative understanding of the biological functions of HTT is lacking, the large number of identified HTT interactors suggests that it serves as a protein-protein interaction hub. Furthermore, Huntington's disease is caused by a mutation in the HTT gene, resulting in a pathogenic expansion of a polyglutamine repeat at the amino terminus of HTT...
March 1, 2018: Nature
https://www.readbyqxmd.com/read/29462355/small-molecule-modulator-of-protein-disulfide-isomerase-attenuates-mutant-huntingtin-toxicity-and-inhibits-endoplasmic-reticulum-stress-in-a-mouse-model-of-huntington-s-disease
#12
Xiao Zhou, Gang Li, Anna Kaplan, Michael M Gaschler, Xiaoyan Zhang, Zhipeng Hou, Mali Jiang, Roseann Zott, Serge Cremers, Brent R Stockwell, Wenzhen Duan
Huntington's disease (HD) is caused by a cytosine-adenine-guanine (CAG) trinucleotide repeat expansion in the huntingtin (HTT) gene encoding an elongated polyglutamine tract within the N-terminal of the huntingtin protein (Htt) and leads to Htt misfolding, aberrant protein aggregation, and progressive appearance of disease symptoms. Chronic activation of endoplasmic reticulum (ER) stress by mutant Htt (mHtt) results in cellular dysfunction and ultimately cell death. Protein disulfide isomerase (PDI) is a chaperone protein located in the ER...
May 1, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29458128/aggregation-prone-regions-in-hypk-help-it-to-form-sequestration-complex-for-toxic-protein-aggregates
#13
Debasish Kumar Ghosh, Ajit Roy, Akash Ranjan
Protein aggregates result from altered structural conformations and they can perturb cellular homeostasis. Prevention mechanisms, which function against protein aggregation by modulatory processes, are diverse and redundant. In this study, we have characterized Huntingtin interacting protein K (HYPK) as a global aggregation-regulatory protein. We report the mechanistic details of how HYPK's aggregation-prone regions allow it to sense and prevent other toxic protein's aggregation by forming unique annular-shaped sequestration complexes...
March 30, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29427099/rna-related-pathology-in-huntington-s-disease
#14
Andreas Neueder, Gillian P Bates
This chapter summarises research investigating the expression of huntingtin sense and anti-sense transcripts, the effect of the mutation on huntingtin processing as well as the more global effect of the mutation on the coding and non-coding transcriptomes. The huntingtin gene is ubiquitously expressed, although expression levels vary between tissues and cell types. A SNP that affects NF-ĸB binding in the huntingtin promoter modulates the expression level of huntingtin transcripts and is associated with the age of disease onset...
2018: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29413175/sirtuins-as-modifiers-of-huntington-s-disease-hd-pathology
#15
Sin Hui Neo, Bor Luen Tang
Sirtuins and their pharmacological activators/inhibitors have been associated with a range of neuroprotective effects or disease modifying influences in neurological disorders. Huntington's disease (HD) is an autosomal-dominant, progressive neurodegenerative disease characterized by movement disorder, psychiatric symptoms and cognitive decline. The monogenic mutation in HD encodes a variant of the protein Huntingtin (HTT). The disease is a consequence of a CAG repeat extension leading to an abnormally long polyglutamine (Q) stretch at HTT's N-terminus, which likely confers a toxic gain of function to the mutant polypeptide...
2018: Progress in Molecular Biology and Translational Science
https://www.readbyqxmd.com/read/29403030/striatal-neurons-directly-converted-from-huntington-s-disease-patient-fibroblasts-recapitulate-age-associated-disease-phenotypes
#16
Matheus B Victor, Michelle Richner, Hannah E Olsen, Seong Won Lee, Alejandro M Monteys, Chunyu Ma, Christine J Huh, Bo Zhang, Beverly L Davidson, X William Yang, Andrew S Yoo
In Huntington's disease (HD), expansion of CAG codons in the huntingtin gene (HTT) leads to the aberrant formation of protein aggregates and the differential degeneration of striatal medium spiny neurons (MSNs). Modeling HD using patient-specific MSNs has been challenging, as neurons differentiated from induced pluripotent stem cells are free of aggregates and lack an overt cell death phenotype. Here we generated MSNs from HD patient fibroblasts through microRNA-based direct neuronal conversion, bypassing the induction of pluripotency and retaining age signatures of the original fibroblasts...
March 2018: Nature Neuroscience
https://www.readbyqxmd.com/read/29399649/sphingomyelin-and-gm1-influence-huntingtin-binding-to-disruption-of-and-aggregation-on-lipid-membranes
#17
Maxmore Chaibva, Xiang Gao, Pranav Jain, Warren A Campbell, Shelli L Frey, Justin Legleiter
Huntington disease (HD) is an inherited neurodegenerative disease caused by the expansion beyond a critical threshold of a polyglutamine (polyQ) tract near the N-terminus of the huntingtin (htt) protein. Expanded polyQ promotes the formation of a variety of oligomeric and fibrillar aggregates of htt that accumulate into the hallmark proteinaceous inclusion bodies associated with HD. htt is also highly associated with numerous cellular and subcellular membranes that contain a variety of lipids. As lipid homeostasis and metabolism abnormalities are observed in HD patients, we investigated how varying both the sphingomyelin (SM) and ganglioside (GM1) contents modifies the interactions between htt and lipid membranes...
January 31, 2018: ACS Omega
https://www.readbyqxmd.com/read/29397067/drp1-phosphorylation-by-mapk1-causes-mitochondrial-dysfunction-in-cell-culture-model-of-huntington-s-disease
#18
Anne Jessica Roe, Xin Qi
Mitochondrial dysfunction is a major cytopathology in Huntington's disease (HD), a fatal and inherited neurodegenerative disease. However, the molecular mechanisms by which the disease-causing gene, mutant Huntingtin (mtHtt), affects mitochondrial function remains elusive. This study aims to determine the role that Mitogen-activated protein kinase 1 (MAPK1) plays in the over-activation of Dynamin-related protein 1 (Drp1), the mitochondrial fission protein, which leads to mitochondrial dysfunction and neurodegeneration seen in HD...
January 24, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29382760/restoring-gabaergic-inhibition-rescues-memory-deficits-in-a-huntington-s-disease-mouse-model
#19
Zahra Dargaei, Jee Yoon Bang, Vivek Mahadevan, C Sahara Khademullah, Simon Bedard, Gustavo Morrone Parfitt, Jun Chul Kim, Melanie A Woodin
Huntington's disease (HD) is classically characterized as a movement disorder, however cognitive impairments precede the motor symptoms by ∼15 y. Based on proteomic and bioinformatic data linking the Huntingtin protein (Htt) and KCC2, which is required for hyperpolarizing GABAergic inhibition, and the important role of inhibition in learning and memory, we hypothesized that aberrant KCC2 function contributes to the hippocampal-associated learning and memory deficits in HD. We discovered that Htt and KCC2 interact in the hippocampi of wild-type and R6/2-HD mice, with a decrease in KCC2 expression in the hippocampus of R6/2 and YAC128 mice...
February 13, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29358329/profilin-reduces-aggregation-and-phase-separation-of-huntingtin-n-terminal-fragments-by-preferentially-binding-to-soluble-monomers-and-oligomers
#20
Ammon E Posey, Kiersten M Ruff, Tyler S Harmon, Scott L Crick, Aimin Li, Marc I Diamond, Rohit V Pappu
Huntingtin N-terminal fragments (Htt-NTFs) with expanded polyglutamine tracts form a range of neurotoxic aggregates that are associated with Huntington's disease. Here, we show that aggregation of Htt-NTFs, irrespective of polyglutamine length, yields at least three phases (designated M, S, and F) that are delineated by sharp concentration thresholds and distinct aggregate sizes and morphologies. We found that monomers and oligomers make up the soluble M phase, ∼25-nm spheres dominate in the soluble S phase, and long, linear fibrils make up the insoluble F phase...
March 9, 2018: Journal of Biological Chemistry
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