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Huntingtins

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https://www.readbyqxmd.com/read/29466333/the-cryo-electron-microscopy-structure-of-huntingtin
#1
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...
February 21, 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
#2
Xiao Zhou, Gang Li, Anna Kaplan, Michael M Gaschler, Xiaoyan Zhang, Zhipeng Hou, Jiang Mali, 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...
February 16, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29460266/increased-levels-of-rictor-prevent-mutant-huntingtin-induced-neuronal-degeneration
#3
Jordi Creus-Muncunill, Laura Rué, Rafael Alcalá-Vida, Raquel Badillos-Rodríguez, Joan Romaní-Aumedes, Sonia Marco, Jordi Alberch, Isabel Perez-Otaño, Cristina Malagelada, Esther Pérez-Navarro
Rictor associates with mTOR to form the mTORC2 complex, which activity regulates neuronal function and survival. Neurodegenerative diseases are characterized by the presence of neuronal dysfunction and cell death in specific brain regions such as for example Huntington's disease (HD), which is characterized by the loss of striatal projection neurons leading to motor dysfunction. Although HD is caused by the expression of mutant huntingtin, cell death occurs gradually suggesting that neurons have the capability to activate compensatory mechanisms to deal with neuronal dysfunction and later cell death...
February 19, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29458128/aggregation-prone-regions-in-hypk-help-it-to-form-sequestration-complex-for-toxic-protein-aggregates
#4
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...
February 16, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29451775/fluorescence-imaging-of-huntingtin-mrna-knockdown
#5
Eunseon Oh, Yuhong Liu, Mahesh V Sonar, Diane Merry, Eric Wickstrom
Huntington's disease (HD) is an autosomal-dominant neurodegenerative genetic disorder caused by CAG repeat expansion in exon 1 of the HTT gene. Expression of the mutant gene results in the production of a neurotoxic polyglutamine (polyQ)-expanded huntingtin (Htt) protein. Clinical trials of knockdown therapy of mutant polyglutamine-encoding HTT mRNA in Huntington's disease (HD) have begun. To measure HTT mRNA knockdown effectiveness in human cells, we utilized a fluorescent hybridization imaging agent specific to the region encompassing the human HTT mRNA initiation codon...
February 16, 2018: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/29440125/small-interfering-rnas-based-on-huntingtin-trinucleotide-repeats-are-highly-toxic-to-cancer-cells
#6
Andrea E Murmann, Quan Q Gao, William E Putzbach, Monal Patel, Elizabeth T Bartom, Calvin Y Law, Bryan Bridgeman, Siquan Chen, Kaylin M McMahon, C Shad Thaxton, Marcus E Peter
Trinucleotide repeat (TNR) expansions in the genome cause a number of degenerative diseases. A prominent TNR expansion involves the triplet CAG in the huntingtin (HTT) gene responsible for Huntington's disease (HD). Pathology is caused by protein and RNA generated from the TNR regions including small siRNA-sized repeat fragments. An inverse correlation between the length of the repeats in HTT and cancer incidence has been reported for HD patients. We now show that siRNAs based on the CAG TNR are toxic to cancer cells by targeting genes that contain long reverse complementary TNRs in their open reading frames...
February 12, 2018: EMBO Reports
https://www.readbyqxmd.com/read/29435951/correction-of-huntington-s-disease-phenotype-by-genistein-induced-autophagy-in-the-cellular-model
#7
Karolina Pierzynowska, Lidia Gaffke, Aleksandra Hać, Jagoda Mantej, Natalia Niedziałek, Joanna Brokowska, Grzegorz Węgrzyn
Huntington's disease (HD) is a monogenic disorder, caused by mutations in the HTT gene which result in expansion of CAG triplets. The product of the mutated gene is misfolded huntingtin protein that forms aggregates leading to impairment of neuronal function, neurodegeneration, motor abnormalities and cognitive deficits. No effective cure is currently available for HD. Here we studied effects of genistein (trihydroxyisoflavone) on a HD cellular model consisting of HEK-293 cells transfected with a plasmid bearing mutated HTT gene...
February 12, 2018: Neuromolecular Medicine
https://www.readbyqxmd.com/read/29433686/gastrodia-elata-alleviates-mutant-huntingtin-aggregation-through-mitochondrial-function-and-biogenesis-mediation
#8
Chuen-Lin Huang, Kaw-Chen Wang, Ying-Chen Yang, Chun-Tang Chiou, Chia-Hui Tan, Yun-Lian Lin, Nai-Kuei Huang
BACKGROUND: According to the Compendium of Materia Medica, Gastrodia elata (GE) Blume is a top-grade herbal medicine frequently used to treat dizziness, headaches, tetanus, and epilepsy, suggesting that it affects neurological functions. Although studies have supported its effects in preventing diverse neurodegenerations such as Huntington's disease (HD), its mechanisms require further investigation. PURPOSE: To investigate the ability of the molecular mechanism of GE to prevent mutant huntingtin (mHTT) protein aggregation by focusing on mitochondrial function and biogenesis, which have been proposed as the therapeutic targets of HD...
January 15, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/29433064/establishing-and-dissolving-cohesion-during-the-vertebrate-cell-cycle
#9
REVIEW
Carmen Morales, Ana Losada
Replicated chromatids are held together from the time they emerge from the replication fork until their separation in anaphase. This process, known as cohesion, promotes faithful DNA repair by homologous recombination in interphase and ensures accurate chromosome segregation in mitosis. Identification of cohesin thirty years ago solved a long-standing question about the nature of the linkage keeping together the sister chromatids. Cohesin is an evolutionarily conserved complex composed of a heterodimer of the Structural Maintenance of Chromosomes (SMC) family of ATPases, Smc1 and Smc3, the kleisin subunit Rad21 and a Huntingtin/EF3/PP2A/Tor1 (HEAT) repeat domain-containing subunit named SA/STAG...
February 9, 2018: Current Opinion in Cell Biology
https://www.readbyqxmd.com/read/29430620/herp-promotes-degradation-of-mutant-huntingtin-involvement-of-the-proteasome-and-molecular-chaperones
#10
Huanhuan Luo, Liying Cao, Xuan Liang, Ana Du, Ting Peng, He Li
In neurodegenerative diseases, pathogenic proteins tend to misfold and form aggregates that are difficult to remove and able to induce excessive endoplasmic reticulum (ER) stress, leading to neuronal injury and apoptosis. Homocysteine-induced endoplasmic reticulum protein (Herp), an E3 ubiquitin ligase, is an important early marker of ER stress and is involved in the ubiquitination and degradation of many neurodegenerative proteins. However, in Huntington's disease (HD), a typical polyglutamine disease, whether Herp is also involved in the metabolism and degradation of the pathogenic protein, mutant huntingtin, has not been reported...
February 12, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29427371/cause-or-compensation-altered-neuronal-ca2-handling-in-huntington-s-disease
#11
REVIEW
James P Mackay, Wissam B Nassrallah, Lynn A Raymond
Huntington's disease (HD) is a hereditary neurodegenerative disorder of typically middle-aged onset for which there is no disease-modifying treatment. Caudate and putamen medium-sized spiny projection neurons (SPNs) most severely degenerate in HD. However, it is unclear why mutant huntingtin protein (mHTT) is preferentially toxic to these neurons or why symptoms manifest only relatively late in life. mHTT interacts with numerous neuronal proteins. Likewise, multiple SPN cellular processes have been described as altered in various HD models...
February 9, 2018: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/29427099/rna-related-pathology-in-huntington-s-disease
#12
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/29427096/clinical-features-of-huntington-s-disease
#13
Rhia Ghosh, Sarah J Tabrizi
Huntington's disease (HD) is the most common monogenic neurodegenerative disease and the commonest genetic dementia in the developed world. With autosomal dominant inheritance, typically mid-life onset, and unrelenting progressive motor, cognitive and psychiatric symptoms over 15-20 years, its impact on patients and their families is devastating. The causative genetic mutation is an expanded CAG trinucleotide repeat in the gene encoding the Huntingtin protein, which leads to a prolonged polyglutamine stretch at the N-terminus of the protein...
2018: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29422836/early-alterations-in-operant-performance-and-prominent-huntingtin-aggregation-in-a-congenic-f344-rat-line-of-the-classical-cagn51trunc-model-of-huntington-disease
#14
Anne-Christine Plank, Fabio Canneva, Kerstin A Raber, Yvonne K Urbach, Julia Dobner, Maja Puchades, Jan G Bjaalie, Clarissa Gillmann, Tobias Bäuerle, Olaf Riess, Hoa H P Nguyen, Stephan von Hörsten
The transgenic rat model of Huntington disease expressing a fragment of mutant HTT (tgHD rat) has been thoroughly characterized and reproduces hallmark symptoms of human adult-onset HD. Pursuing the optimization of this model for evaluation of translational therapeutic approaches, the F344 inbred rat strain was considered as advantageous genetic background for the expression of the HD transgenic construct. In the present study, a novel congenic line of the SPRDtgHD transgenic model of HD, carrying 51 CAG repeats, was generated on the F344 rat genetic background...
2018: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/29422655/glycogen-synthase-protects-neurons-from-cytotoxicity-of-mutant-huntingtin-by-enhancing-the-autophagy-flux
#15
Anupama Rai, Pankaj Kumar Singh, Virender Singh, Vipendra Kumar, Rohit Mishra, Ashwani Kumar Thakur, Anita Mahadevan, Susarla Krishna Shankar, Nihar Ranjan Jana, Subramaniam Ganesh
Healthy neurons do not store glycogen while they do possess the machinery for the glycogen synthesis albeit at an inactive state. Neurons in the degenerating brain, however, are known to accumulate glycogen, although its significance was not well understood. Emerging reports present contrasting views on neuronal glycogen synthesis; a few reports demonstrate a neurotoxic effect of glycogen while a few others suggest glycogen to be neuroprotective. Thus, the specific role of glycogen and glycogen synthase in neuronal physiology is largely unexplored...
February 8, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29415038/bachd-rats-expressing-full-length-mutant-huntingtin-exhibit-differences-in-social-behavior-compared-to-wild-type-littermates
#16
Giuseppe Manfré, Arianna Novati, Ilaria Faccini, Andrea C Rossetti, Kari Bosch, Raffaella Molteni, Marco A Riva, Johanneke E Van der Harst, Huu Phuc Nguyen, Judith R Homberg
BACKGROUND: Huntington disease (HD) is a devastating inherited neurodegenerative disorder characterized by progressive motor, cognitive, and psychiatric symptoms without any cure to slow down or stop the progress of the disease. The BACHD rat model for HD carrying the human full-length mutant huntingtin protein (mHTT) with 97 polyQ repeats has been recently established as a promising model which reproduces several HD-like features. While motor and cognitive functions have been characterized in BACHD rats, little is known about their social phenotype...
2018: PloS One
https://www.readbyqxmd.com/read/29413175/sirtuins-as-modifiers-of-huntington-s-disease-hd-pathology
#17
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
#18
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...
February 5, 2018: Nature Neuroscience
https://www.readbyqxmd.com/read/29401586/polyq-expanded-huntingtin-and-ataxin-3-sequester-ubiquitin-adaptors-hhr23b-and-ubqln2-into-aggregates-via-conjugated-ubiquitin
#19
Hui Yang, Hong-Wei Yue, Wen-Tian He, Jun-Ye Hong, Lei-Lei Jiang, Hong-Yu Hu
The components of ubiquitin (Ub)-proteasome system, such as Ub, Ub adaptors, or proteasome subunits, are commonly accumulated with the aggregated proteins in inclusions, but how protein aggregates sequester Ub-related proteins remains elusive. Using N-terminal huntingtin (Htt-N552) and ataxin (Atx)-3 as model proteins, we investigated the molecular mechanism underlying sequestration of Ub adaptors by polyQ-expanded proteins. We found that polyQ-expanded Htt-N552 and Atx-3 sequester endogenous Ub adaptors, human RAD23 homolog B (hHR23B) and ubiquilin (UBQLN)-2, into inclusions...
January 11, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29399649/sphingomyelin-and-gm1-influence-huntingtin-binding-to-disruption-of-and-aggregation-on-lipid-membranes
#20
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
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