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https://www.readbyqxmd.com/read/28938121/huntingtin-fibrils-poke-membranes
#1
Pedro Guedes-Dias, Erika L F Holzbaur
A hallmark of Huntington's disease is the presence of intracellular aggregates of mutant huntingtin, the pathological significance of which has long been debated. Using cryo-electron tomography, Bauerlein et al. reveal the fibrillary structure of huntingtin aggregates in situ and show that huntingtin fibrils interact with the endoplasmic reticulum, distorting its morphology and dynamics.
September 21, 2017: Cell
https://www.readbyqxmd.com/read/28937758/monomeric-huntingtin-exon-1-has-similar-overall-structural-features-for-wild-type-and-pathological-polyglutamine-lengths
#2
John B Warner, Kiersten Ruff, Piau Siong Tan, Edward A Lemke, Rohit V Pappu, Hilal A Lashuel
Huntington's disease is caused by expansion of a polyglutamine (polyQ) domain within exon 1 of the huntingtin gene (Httex1). A popular hypothesis is that the Httex1 protein undergoes sharp conformational changes as the polyQ length exceeds a threshold of 36 residues. We test this hypothesis by combining novel semi-synthesis strategies with state-of-the-art single molecule Förster resonance energy transfer measurements on biologically relevant Httex1 proteins of five different polyQ lengths. Our results, integrated with atomistic simulations, negate the hypothesis of a sharp, polyQ length-dependent change in the structure of monomeric Httex1...
September 22, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28934397/a-modifier-of-huntington-s-disease-onset-at-the-mlh1-locus
#3
Jong-Min Lee, Michael J Chao, Denise Harold, Kawther Abu Elneel, Tammy Gillis, Peter Holmans, Lesley Jones, Michael Orth, Richard H Myers, Seung Kwak, Vanessa C Wheeler, Marcy E MacDonald, James F Gusella
Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by an expanded CAG repeat in HTT. Many clinical characteristics of HD such as age at motor onset are determined largely by the size of HTT CAG repeat. However, emerging evidence strongly supports a role for other genetic factors in modifying the disease pathogenesis driven by mutant huntingtin. A recent genome-wide association analysis to discover genetic modifiers of HD onset age provided initial evidence for modifier loci on chromosomes 8 and 15 and suggestive evidence for a locus on chromosome 3...
October 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28934390/protein-phosphatase-1-regulates-huntingtin-exon-1-aggregation-and-toxicity
#4
Joana Branco-Santos, Federico Herrera, Gonçalo M Poças, Yolanda Pires-Afonso, Flaviano Giorgini, Pedro M Domingos, Tiago F Outeiro
Huntington's disease is neurodegenerative disorder caused by a polyglutamine expansion in the N-terminal region of the huntingtin protein (N17). Here, we analysed the relative contribution of each phosphorylatable residue in the N17 region (T3, S13 and S16) towards huntingtin exon 1 (HTTex1) oligomerization, aggregation and toxicity in human cells and Drosophila neurons. We used bimolecular fluorescence complementation to show that expression of single phosphomimic mutations completely abolished HTTex1 aggregation in human cells...
October 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28930690/the-self-inactivating-kamicas9-system-for-the-editing-of-cns-disease-genes
#5
Nicolas Merienne, Gabriel Vachey, Lucie de Longprez, Cécile Meunier, Virginie Zimmer, Guillaume Perriard, Mathieu Canales, Amandine Mathias, Lucas Herrgott, Tim Beltraminelli, Axelle Maulet, Thomas Dequesne, Catherine Pythoud, Maria Rey, Luc Pellerin, Emmanuel Brouillet, Anselme L Perrier, Renaud du Pasquier, Nicole Déglon
Neurodegenerative disorders are a major public health problem because of the high frequency of these diseases. Genome editing with the CRISPR/Cas9 system is making it possible to modify the sequence of genes linked to these disorders. We designed the KamiCas9 self-inactivating editing system to achieve transient expression of the Cas9 protein and high editing efficiency. In the first application, the gene responsible for Huntington's disease (HD) was targeted in adult mouse neuronal and glial cells. Mutant huntingtin (HTT) was efficiently inactivated in mouse models of HD, leading to an improvement in key markers of the disease...
September 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/28927719/sex-dependent-behavioral-impairments-in-the-hdhq350-mouse-line
#6
Jessica K Cao, Peter J Detloff, Richard G Gardner, Nephi Stella
Huntington's Disease (HD) is an autosomal dominant neurodegenerative disease characterized by gradual deterioration of motor and cognitive functions and development of psychiatric deficits. Animal models provide powerful means to study the pathological processes, molecular dysfunctions and symptoms associated with HD. We performed a longitudinal behavioral study of the newly developed HdhQ350/+ mouse line, a knock-in model that expresses a repeat of 350 glutamines. We found remarkable sex-dependent differences on symptom onset and severity...
September 16, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28920889/therapies-targeting-dna-and-rna-in-huntington-s-disease
#7
REVIEW
Edward J Wild, Sarah J Tabrizi
No disease-slowing treatment exists for Huntington's disease, but its monogenic inheritance makes it an appealing candidate for the development of therapies targeting processes close to its genetic cause. Huntington's disease is caused by CAG repeat expansions in the HTT gene, which encodes the huntingtin protein; development of therapies to target HTT transcription and the translation of its mRNA is therefore an area of intense investigation. Huntingtin-lowering strategies include antisense oligonucleotides and RNA interference targeting mRNA, and zinc finger transcriptional repressors and CRISPR-Cas9 methods aiming to reduce transcription by targeting DNA...
October 2017: Lancet Neurology
https://www.readbyqxmd.com/read/28920551/a-comprehensive-in-silico-analysis-of-huntingtin-and-its-interactome
#8
Valentina Brandi, Valentina Di Lella, Maria Marino, Paolo Ascenzi, Fabio Polticelli
A polyglutamine expansion of the N-terminal region of huntingtin (Htt) causes Huntington's disease (HD), a severe neurodegenerative disorder. Htt huge multidomain structure, the presence of disordered regions, and the lack of sequence homologs of known structure, so far prevented structural studies of Htt, making the study of its structure-function relationships very difficult. In this work, the presence and location of five Htt ordered domains (named from Hunt1 to Hunt5) has been detected and the structure of these domains has been predicted for the first time using a combined threading/ab initio modelling approach...
September 18, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28920088/metabolic-and-transcriptomic-analysis-of-huntington-s-disease-model-reveal-changes-in-intracellular-glucose-levels-and-related-genes
#9
Gepoliano Chaves, Rıfat Emrah Özel, Namrata V Rao, Hana Hadiprodjo, Yvonne Da Costa, Zachary Tokuno, Nader Pourmand
Huntington's Disease (HD) is a neurodegenerative disorder caused by an expansion in a CAG-tri-nucleotide repeat that introduces a poly-glutamine stretch into the huntingtin protein (mHTT). Mutant huntingtin (mHTT) has been associated with several phenotypes including mood disorders and depression. Additionally, HD patients are known to be more susceptible to type II diabetes mellitus (T2DM), and HD mice model develops diabetes. However, the mechanism and pathways that link Huntington's disease and diabetes have not been well established...
August 2017: Heliyon
https://www.readbyqxmd.com/read/28900136/differential-effects-of-soluble-and-aggregating-polyq-proteins-on-cytotoxicity-and-type-1-myosin-dependent-endocytosis-in-yeast
#10
Lisa L Berglund, Xinxin Hao, Beidong Liu, Julie Grantham, Thomas Nyström
Huntington's disease develops when the polyglutamine (polyQ) repeat in the Huntingtin (Htt) protein is expanded to over 35 glutamines rendering it aggregation-prone. Here, using Htt exon-1 as a polyQ model protein in a genome-wide screen in yeast, we show that the normal and soluble Htt exon-1 is toxic in cells with defects in type-1 myosin-dependent endocytosis. The toxicity of Htt is linked to physical interactions with type-1 myosins, which occur via the Htt proline-rich region, leading to a reduction in actin patch polarization and clathrin-dependent endocytosis...
September 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28900094/-protein-protein-interactions-of-huntingtin-in-the-hippocampus
#11
A L Proskura, S O Vechkapova, T A Zapara, A S Ratushniak
Huntingtin (HTT) occurs in the neuronal cytoplasm and can interact with structural elements of synapses. Huntington's disease (HD) results from pathological expansion of a polyglutamine stretch in the HTT molecule, being probably associated with aberrant protein-protein interactions. The pathogenetic mechanism is still incompletely understood. Alterations of the synaptic structure and plasticity in the hippocampus are observed in early HD. The objective of the study was to theoretically evaluate the HTT contribution to changes in synaptic plasticity by integrating the available experimental data...
July 2017: Molekuliarnaia Biologiia
https://www.readbyqxmd.com/read/28893927/mutant-huntingtin-inhibits-%C3%AE-b-crystallin-expression-and-impairs-exosome-secretion-from-astrocytes
#12
Yan Hong, Ting Zhao, Xiao-Jiang Li, Shihua Li
In the brain, astrocytes secrete diverse substances that regulate neuronal function and viability. Exosomes, which are vesicles produced through the formation of multivesicular bodies and their subsequent fusion with the plasma membrane, are also released from astrocytes via exocytotic secretion. Astrocytic exosomes carry heat shock proteins that can reduce the cellular toxicity of misfolded proteins and prevent neurodegeneration. Although mutant huntingtin (mHtt) affects multiple functions of astrocytes, it remains unknown whether mHtt impairs the production of exosomes from astrocytes...
September 11, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28890085/in-situ-architecture-and-cellular-interactions-of-polyq-inclusions
#13
Felix J B Bäuerlein, Itika Saha, Archana Mishra, Maria Kalemanov, Antonio Martínez-Sánchez, Rüdiger Klein, Irina Dudanova, Mark S Hipp, F Ulrich Hartl, Wolfgang Baumeister, Rubén Fernández-Busnadiego
Expression of many disease-related aggregation-prone proteins results in cytotoxicity and the formation of large intracellular inclusion bodies. To gain insight into the role of inclusions in pathology and the in situ structure of protein aggregates inside cells, we employ advanced cryo-electron tomography methods to analyze the structure of inclusions formed by polyglutamine (polyQ)-expanded huntingtin exon 1 within their intact cellular context. In primary mouse neurons and immortalized human cells, polyQ inclusions consist of amyloid-like fibrils that interact with cellular endomembranes, particularly of the endoplasmic reticulum (ER)...
September 21, 2017: Cell
https://www.readbyqxmd.com/read/28889265/manganese-and-the-insulin-igf-signaling-network-in-huntington-s-disease-and-other-neurodegenerative-disorders
#14
Miles R Bryan, Aaron B Bowman
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease resulting in motor impairment and death in patients. Recently, several studies have demonstrated insulin or insulin-like growth factor (IGF) treatment in models of HD, resulting in potent amelioration of HD phenotypes via modulation of the PI3K/AKT/mTOR pathways. Administration of IGF and insulin can rescue microtubule transport, metabolic function, and autophagy defects, resulting in clearance of Huntingtin (HTT) aggregates, restoration of mitochondrial function, amelioration of motor abnormalities, and enhanced survival...
2017: Advances in Neurobiology
https://www.readbyqxmd.com/read/28871787/nmr-spectroscopy-based-metabolomics-of-drosophila-model-of-huntington-s-disease-suggests-altered-cell-energetics
#15
Virender Singh, Raj Kumar Sharma, Thamarailingam Athilingam, Pradip Sinha, Neeraj Sinha, Ashwani Kumar Thakur
Huntington's disease (HD) is a neurodegenerative disorder induced by aggregation of the pathological form of Huntingtin protein that has expanded polyglutamine (polyQ) repeats. In the Drosophila model, for instance, expression of transgenes with polyQ repeats induce HD-like pathologies progressively correlating with the increasing lengths of these repeats. Previous studies on both animal models and clinical samples have revealed metabolite imbalances during HD progression. To further explore the physiological processes linked to metabolite imbalances during HD, we have investigated 1D (1)H NMR spectroscopy-based metabolomics profile of Drosophila HD model...
September 5, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/28869595/a-toxic-mutant-huntingtin-species-is-resistant-to-selective-autophagy
#16
Yuhua Fu, Peng Wu, Yuyin Pan, Xiaoli Sun, Huiya Yang, Marian Difiglia, Boxun Lu
Protein misfolding is a common theme in neurodegenerative disorders including Huntington's disease (HD). The HD-causing mutant huntingtin protein (mHTT) has an expanded polyglutamine (polyQ) stretch that may adopt multiple conformations, and the most toxic of these is the one recognized by antibody 3B5H10. Here we show that the 3B5H10-recognized mHTT species has a slower degradation rate due to its resistance to selective autophagy in human cells and brains, revealing mechanisms of its higher toxicity.
September 4, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28864412/role-of-the-ribosomal-quality-control-machinery-in-nucleocytoplasmic-translocation-of-polyq-expanded-huntingtin-exon-1
#17
Ju Zheng, Junsheng Yang, Young-Jun Choe, Xinxin Hao, Xiuling Cao, Qian Zhao, Yuejie Zhang, Vanessa Franssens, F Ulrich Hartl, Thomas Nyström, Joris Winderickx, Beidong Liu
The subcellular localization of polyQ-expanded huntingtin exon1 (Httex1) modulates polyQ toxicity in models of Huntington's disease. Using genome-wide screens in a yeast model system, we report that the ribosome quality control (RQC) machinery, recently implicated in neurodegeneration, is a key determinant for the nucleocytoplasmic distribution of Httex1-103Q. Deletion of the RQC genes, LTN1 or RQC1, caused the accumulation of Httex1-103Q in the nucleus through a process that required the CAT-tail tagging activity of Rqc2 and transport via the nuclear pore complex...
August 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28861715/the-neuroprotective-transcription-factor-atf5-is-decreased-and-sequestered-into-polyglutamine-inclusions-in-huntington-s-disease
#18
Ivó H Hernández, Jesús Torres-Peraza, María Santos-Galindo, Eloísa Ramos-Morón, M Rosario Fernández-Fernández, María J Pérez-Álvarez, Antonio Miranda-Vizuete, José J Lucas
Activating transcription factor-5 (ATF5) is a stress-response transcription factor induced upon different cell stressors like fasting, amino-acid limitation, cadmium or arsenite. ATF5 is also induced, and promotes transcription of anti-apoptotic target genes like MCL1, during the unfolded protein response (UPR) triggered by endoplasmic reticulum stress. In the brain, high ATF5 levels are found in gliomas and also in neural progenitor cells, which need to decrease their ATF5 levels for differentiation into mature neurons or glia...
August 31, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28858902/huntington-mice-demonstrate-diminished-pain-response-in-inflammatory-pain-model
#19
Ya-Chi Lin, Hung-Tsung Hsiao, Sheng-Nan Wu, Yen-Chin Liu
BACKGROUND: Huntington disease (HD) affects the nervous system and leads to mental and motor dysfunction. Previous studies have shown that HD is caused by the exon 1 region of the huntingtin (HTT) gene having expanded CAG trinucleotide repeats. However, few studies have focused on the relationship between HD and pain. The purpose of this study is to investigate the relationship between HD and pain response. METHODS: We used clinical similar transgenic HD mice carrying a mutant HTT exon 1 containing 84 CAG trinucleotide repeats to evaluate the relationship between HD and pain...
August 30, 2017: Anesthesia and Analgesia
https://www.readbyqxmd.com/read/28853159/tetrahydrocannabinolic-acid-is-a-potent-ppar%C3%AE-agonist-with-neuroprotective-activity
#20
Xavier Nadal, Carmen Del Río, Salvatore Casano, Belén Palomares, Carlos Ferreiro-Vera, Carmen Navarrete, Carolina Sánchez-Carnerero, Irene Cantarero, M Luz Bellido, Stefan Meyer, Gaetano Morello, Giovanni Appendino, Eduardo Muñoz
BACKGROUND AND PURPOSE: Phytocannabinoids are produced in Cannabis sativa L. in acidic form and are decarboxylated upon heating, processing, and storage. While the biological effects of decarboxylated cannabinoids such as Δ(9) -tetrahydrocannabinol (Δ(9) -THC) have been extensively investigated, the bioactivity of Δ(9) -THCA is largely unknown, despite its occurrence in different Cannabis preparations. The aim of this study was to determine whether Δ(9) -THCA modulates the PPARγ pathway and has neuroprotective activity EXPERIMENTAL APPROACH: The effects of six phytocannabinoids on PPARγ binding and transcriptional activity were investigated...
August 29, 2017: British Journal of Pharmacology
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