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Huntingtin disease

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https://www.readbyqxmd.com/read/28104789/a-novel-humanized-mouse-model-of-huntington-disease-for-preclinical-development-of-therapeutics-targeting-mutant-huntingtin-alleles
#1
Amber L Southwell, Niels H Skotte, Erika B Villanueva, Michael E Østergaard, Xiaofeng Gu, Holly B Kordasiewicz, Chris Kay, Daphne Cheung, Yuanyun Xie, Sabine Waltl, Louisa Dal Cengio, Hailey Findlay-Black, Crystal N Doty, Eugenia Petoukhov, Diepiriye Iworima, Ramy Slama, Jolene Ooi, Mahmoud A Pouladi, William X Yang, Eric E Swayze, Punit P Seth, Michael R Hayden
Huntington disease (HD) is a neurodegenerative disease caused by a mutation in the huntingtin (HTT) gene. HTT is a large protein, interacts with many partners and is involved in many cellular pathways, which are perturbed in HD. Therapies targeting HTT directly are likely to provide the most global benefit. Thus there is a need for preclinical models of HD recapitulating human HTT genetics. We previously generated a humanized mouse model of HD, Hu97/18, by intercrossing BACHD and YAC18 mice with knockout of the endogenous mouse HD homolog (Hdh)...
January 18, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28102321/the-chaperonin-cct-inhibits-assembly-of-%C3%AE-synuclein-amyloid-fibrils-by-a-specific-conformation-dependent-interaction
#2
Begoña Sot, Alejandra Rubio-Muñoz, Ahudrey Leal-Quintero, Javier Martínez-Sabando, Miguel Marcilla, Cintia Roodveldt, José M Valpuesta
The eukaryotic chaperonin CCT (chaperonin containing TCP-1) uses cavities built into its double-ring structure to encapsulate and to assist folding of a large subset of proteins. CCT can inhibit amyloid fibre assembly and toxicity of the polyQ extended mutant of huntingtin, the protein responsible for Huntington's disease. This raises the possibility that CCT modulates other amyloidopathies, a still-unaddressed question. We show here that CCT inhibits amyloid fibre assembly of α-synuclein A53T, one of the mutants responsible for Parkinson's disease...
January 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28099507/correlations-of-behavioral-deficits-with-brain-pathology-assessed-through-longitudinal-mri-and-histopathology-in-the-hdhq150-q150-mouse-model-of-huntington-s-disease
#3
Ivan Rattray, Edward J Smith, William R Crum, Thomas A Walker, Richard Gale, Gillian P Bates, Michel Modo
A variety of mouse models have been developed that express mutant huntingtin (mHTT) leading to aggregates and inclusions that model the molecular pathology observed in Huntington's disease. Here we show that although homozygous HdhQ150 knock-in mice developed motor impairments (rotarod, locomotor activity, grip strength) by 36 weeks of age, cognitive dysfunction (swimming T maze, fear conditioning, odor discrimination, social interaction) was not evident by 94 weeks. Concomitant to behavioral assessments, T2-weighted MRI volume measurements indicated a slower striatal growth with a significant difference between wild type (WT) and HdhQ150 mice being present even at 15 weeks...
2017: PloS One
https://www.readbyqxmd.com/read/28096245/prion-like-characteristics-of-polyglutamine-containing-proteins
#4
Margaret M P Pearce, Ron R Kopito
Transmissible spongiform encephalopathies are infectious neurodegenerative diseases caused by the conversion of prion protein (PrP) into a self-replicating conformation that spreads via templated conversion of natively folded PrP molecules within or between cells. Recent studies provide compelling evidence that prion-like behavior is a general property of most protein aggregates associated with neurodegenerative diseases. Many of these disorders are associated with spontaneous protein aggregation, but genetic mutations can increase the aggregation propensity of specific proteins, including expansion of polyglutamine (polyQ) tracts, which is causative of nine inherited neurodegenerative diseases...
January 17, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28094373/conformational-dynamics-and-self-association-of-intrinsically-disordered-huntingtin-exon-1-in-cells
#5
Steffen Büning, Abhishek Sharma, Shivang Vachharajani, Estella Newcombe, Angelique Ormsby, Mimi Gao, David Gnutt, Tobias Vöpel, Danny M Hatters, Simon Ebbinghaus
Huntington's disease is caused by a CAG trinucleotide expansion mutation in the Huntingtin gene that leads to an artificially long polyglutamine sequence in the Huntingtin protein. A key feature of the disease is the intracellular aggregation of the Huntingtin exon 1 protein (Httex1) into micrometer sized inclusion bodies. The aggregation process of Httex1 has been extensively studied in vitro, however, the crucial early events of nucleation and aggregation in the cell remain elusive. Here, we studied the conformational dynamics and self-association of Httex1 by in-cell experiments using laser-induced temperature jumps and analytical ultracentrifugation...
January 17, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28087715/sf3b1-hsh155-heat-motif-mutations-affect-interaction-with-the-spliceosomal-atpase-prp5-resulting-in-altered-branch-site-selectivity-in-pre-mrna-splicing
#6
Qing Tang, Susana Rodriguez-Santiago, Jing Wang, Jia Pu, Andrea Yuste, Varun Gupta, Alberto Moldón, Yong-Zhen Xu, Charles C Query
Mutations in the U2 snRNP component SF3B1 are prominent in myelodysplastic syndromes (MDSs) and other cancers and have been shown recently to alter branch site (BS) or 3' splice site selection in splicing. However, the molecular mechanism of altered splicing is not known. We show here that hsh155 mutant alleles in Saccharomyces cerevisiae, counterparts of SF3B1 mutations frequently found in cancers, specifically change splicing of suboptimal BS pre-mRNA substrates. We found that Hsh155p interacts directly with Prp5p, the first ATPase that acts during spliceosome assembly, and localized the interacting regions to HEAT (Huntingtin, EF3, PP2A, and TOR1) motifs in SF3B1 associated with disease mutations...
December 15, 2016: Genes & Development
https://www.readbyqxmd.com/read/28069792/targeting-ent1-and-adenosine-tone-for-the-treatment-of-huntington-s-disease
#7
Yu-Han Kao, Meng-Syuan Lin, Chiung-Mei Chen, Yih-Ru Wu, Hui-Mei Chen, Hsing-Lin Lai, Yijuang Chern, Chun-Jung Lin
Huntington's disease (HD) is caused by an abnormal CAG expansion in the exon 1 of huntingtin gene. The treatment of HD is an unmet medical need. Given the important role of adenosine in modulating brain activity, in this study, levels of adenosine and adenine nucleotides in the cerebral spinal fluid of patients with HD and in the brain of two mouse models of HD (R6/2 and Hdh(150Q)) were analysed. The expression and activity of ENT1 in the striatum of mice with HD were measured. Targeting adenosine tone for treating HD was examined in R6/2 mice by genetic removal of ENT1 and by giving an ENT1 inhibitor, respectively...
January 9, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28032313/development-of-research-on-huntington-disease-in-china
#8
REVIEW
Hong-Lei Li, Yan-Bin Zhang, Zhi-Ying Wu
Huntington disease (HD) is a progressive autosomal dominantly inherited neurodegenerative disorder, characterized with the typical manifestations of involuntary movements, cognitive dysfunction, and psychiatric or behavioral disturbance. It results from an expansion in the number of CAG repeats in the first exon of the huntingtin (HTT) gene. In China, since the first case report in 1959, the knowledge of this disorder has been involving a lot, especially in the latest decade. In this review, we meta-analysis and summarize the research reports that were published by Chinese researchers since 1959, so that researchers whose native language were not Chinese can get a general idea of the research development of HD in China...
December 28, 2016: Neuroscience Bulletin
https://www.readbyqxmd.com/read/28027448/induced-pluripotent-hd-monkey-stem-cells-derived-neural-cells-for-drug-discovery
#9
Tanut Kunkanjanawan, Richard Carter, Kwan-Sung Ahn, Jinjing Yang, Rangsun Parnpai, Anthony W S Chan
Huntington's disease (HD) is a neurodegenerative disease caused by an expansion of CAG trinucleotide repeat (polyglutamine [polyQ]) in the huntingtin ( HTT) gene, which leads to the formation of mutant HTT (mHTT) protein aggregates. In the nervous system, an accumulation of mHTT protein results in glutamate-mediated excitotoxicity, proteosome instability, and apoptosis. Although HD pathogenesis has been extensively studied, effective treatment of HD has yet to be developed. Therapeutic discovery research in HD has been reported using yeast, cells derived from transgenic animal models and HD patients, and induced pluripotent stem cells from patients...
December 1, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/28017939/huntingtin-is-a-scaffolding-protein-in-the-atm-oxidative-dna-damage-response-complex
#10
Tamara Maiuri, Andrew J Mocle, Claudia L Hung, Jianrun Xia, Willeke M C van Roon-Mom, Ray Truant
Huntington's disease (HD) is an age-dependent neurodegenerative disease. DNA repair pathways have recently been implicated as the most predominant modifiers of age of onset in HD patients. We report that endogenous huntingtin protein directly participates in oxidative DNA damage repair. Using novel chromobodies to detect endogenous human huntingtin in live cells, we show that localization of huntingtin to DNA damage sites is dependent on the kinase activity of ataxia telangiectasia mutated (ATM) protein. Super-resolution microscopy and biochemical assays revealed that huntingtin co-localizes with and scaffolds proteins of the DNA damage response pathway in response to oxidative stress...
December 25, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/28017473/huntingtin-mediated-multipolar-bipolar-transition-of-newborn-cortical-neurons-is-critical-for-their-postnatal-neuronal-morphology
#11
Monia Barnat, Julien Le Friec, Caroline Benstaali, Sandrine Humbert
In the developing cortex, projection neurons undergo multipolar-bipolar transition, radial-directed migration, and maturation. The contribution of these developmental steps to the structure of the adult cortex is not completely understood. Here, we report that huntingtin (HTT), the protein mutated in Huntington's disease, is enriched in polarizing projection neurons. The depletion of HTT in postmitotic projection neurons leads to the mislocalization of layer-specific neuronal populations in the mouse neocortex...
January 4, 2017: Neuron
https://www.readbyqxmd.com/read/28007908/topoisomerase-1-inhibitor-topotecan-delays-the-disease-progression-in-a-mouse-model-of-huntington-s-disease
#12
Shashi Shekhar, Naman Vatsa, Vipendra Kumar, Brijesh Kumar Singh, Imran Jamal, Ankit Sharma, Nihar Ranjan Jana
Huntington's disease (HD) is a dominantly inherited progressive neurodegenerative disorder caused by the accumulation of polyglutamine expanded mutant huntingtin as inclusion bodies primarily in the brain. After the discovery of the HD gene, considerable progress has been made in understanding the disease pathogenesis and multiple drug targets have been identified, even though currently there is no effective therapy. Here, we demonstrate that the treatment of topotecan, a brain-penetrating topoisomerase 1 inhibitor, to HD transgenic mouse considerably improved its motor behavioural abnormalities along with a significant extension of lifespan...
December 22, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/28000697/the-targetable-a1-huntington-disease-haplotype-has-distinct-amerindian-and-european-origins-in-latin-america
#13
Chris Kay, Indira Tirado-Hurtado, Mario Cornejo-Olivas, Jennifer A Collins, Galen Wright, Miguel Inca-Martinez, Diego Veliz-Otani, Maria E Ketelaar, Ramy A Slama, Colin J Ross, Pilar Mazzetti, Michael R Hayden
Huntington disease (HD) is a dominant neurodegenerative disorder caused by a CAG repeat expansion in the Huntingtin (HTT) gene. HD occurs worldwide, but the causative mutation is found on different HTT haplotypes in distinct ethnic groups. In Latin America, HD is thought to have European origins, but indigenous Amerindian ancestry has not been investigated. Here, we report dense HTT haplotypes in 62 mestizo Peruvian HD families, 17 HD families from across Latin America, and 42 controls of defined Peruvian Amerindian ethnicity to determine the origin of HD in populations of admixed Amerindian and European descent...
December 21, 2016: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/27992085/muscle-atrophy-is-associated-with-cervical-spinal-motoneuron-loss-in-bachd-mouse-model-for-huntington-s-disease
#14
Priscila Aparecida Costa Valadão, Bárbara Campos de Aragão, Jéssica Neves Andrade, Matheus Proença S M Gomes, Giselle Foureaux, Julliane Vasconcelos Joviano-Santos, José Carlos Nogueira, Fabíola Mara Ribeiro, Juan Carlos Tapia, Cristina Guatimosim
Involuntary choreiform movements are clinical hallmark of Huntington's disease, an autosomal dominant neurodegenerative disorder caused by an increased number of CAG trinucleotide repeats in the huntingtin gene. Involuntary movements start with an impairment of facial muscles and then affect trunk and limbs muscles. Huntington's disease symptoms are caused by changes in cortex and striatum neurons induced by mutated huntingtin. However little is known about the impact of this abnormal protein in spinal cord motoneurons that control movement...
December 19, 2016: European Journal of Neuroscience
https://www.readbyqxmd.com/read/27989401/cbp-p300-bromodomains-regulate-amyloid-like-protein-aggregation-upon-aberrant-lysine-acetylation
#15
Heidi Olzscha, Oleg Fedorov, Benedikt M Kessler, Stefan Knapp, Nicholas B La Thangue
Lysine acetylation is becoming increasingly recognized as a general biological principle in cellular homeostasis, and is subject to abnormal control in different human pathologies. Here, we describe a global effect on amyloid-like protein aggregation in human cells that results from aberrant lysine acetylation. Bromodomain reader proteins are involved in the aggregation process and, using chemical biology and gene silencing, we establish that p300/CBP bromodomains are necessary for aggregation to occur. Moreover, protein aggregation disturbs proteostasis by impairing the ubiquitin proteasome system (UPS) and protein translation, resulting in decreased cell viability...
January 19, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/27988204/smad-transcription-factors-are-altered-in-cell-models-of-hd-and-regulate-htt-expression
#16
K R Bowles, T Stone, P Holmans, N D Allen, S B Dunnett, L Jones
Transcriptional dysregulation is observable in multiple animal and cell models of Huntington's disease, as well as in human blood and post-mortem caudate. This contributes to HD pathogenesis, although the exact mechanism by which this occurs is unknown. We therefore utilised a dynamic model in order to determine the differential effect of growth factor stimulation on gene expression, to highlight potential alterations in kinase signalling pathways that may be in part responsible for the transcriptional dysregulation observed in HD, and which may reveal new therapeutic targets...
December 14, 2016: Cellular Signalling
https://www.readbyqxmd.com/read/27984179/immunohistochemical-analysis-of-huntingtin-associated-protein-1in-adult-rat-spinal-cord-and-its-regional-relationship-with-androgen-receptor
#17
Md Nabiul Islam, Yukio Takeshita, Akie Yanai, Amami Imagawa, Mir Rubayet Jahan, Greggory Wroblewski, Joe Nemoto, Ryutaro Fujinaga, Koh Shinoda
Huntingtin-associated protein 1 (HAP1) is a neuronal interactor with causatively polyglutamine (polyQ)-expanded huntingtin in Huntington's disease and also associated with pathologically polyQ-expanded androgen receptor (AR) in spinobulbar muscular atrophy (SBMA), being considered as a protective factor against neurodegenerative apoptosis. In normal brains, it is abundantly expressed particularly in the limbic-hypothalamic regions that tend to be spared from neurodegeneration, whereas the areas with little HAP1 expression, including the striatum, thalamus, cerebral neocortex and cerebellum, are targets in several neurodegenerative diseases...
October 28, 2016: Neuroscience
https://www.readbyqxmd.com/read/27957684/huntingtin-polyq-mutation-impairs-the-17%C3%AE-estradiol-neuroglobin-pathway-devoted-to-neuron-survival
#18
Maria Teresa Nuzzo, Marco Fiocchetti, Pierangela Totta, Mariarosa A B Melone, Antonella Cardinale, Francesca R Fusco, Stefano Gustincich, Francesca Persichetti, Paolo Ascenzi, Maria Marino
Among several mechanisms underlying the well-known trophic and protective effects of 17β-estradiol (E2) in the brain, we recently reported that E2 induces the up-regulation of two anti-apoptotic and neuroprotectant proteins: huntingtin (HTT) and neuroglobin (NGB). Here, we investigate the role of this up-regulation. The obtained results indicate that E2 promotes NGB-HTT association, induces the localization of the complex at the mitochondria, and protects SK-N-BE neuroblastoma cells and murine striatal cells, which express wild-type HTT (i...
December 12, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27940602/huntington-s-disease-mechanisms-of-pathogenesis-and-therapeutic-strategies
#19
Maria Jimenez-Sanchez, Floriana Licitra, Benjamin R Underwood, David C Rubinsztein
Huntington's disease is a late-onset neurodegenerative disease caused by a CAG trinucleotide repeat in the gene encoding the huntingtin protein. Despite its well-defined genetic origin, the molecular and cellular mechanisms underlying the disease are unclear and complex. Here, we review some of the currently known functions of the wild-type huntingtin protein and discuss the deleterious effects that arise from the expansion of the CAG repeats, which are translated into an abnormally long polyglutamine tract...
December 9, 2016: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/27939523/effect-of-praeruptorin-c-on-3-nitropropionic-acid-induced-huntington-s-disease-like-symptoms-in-mice
#20
Lu Wang, Jing Wang, Le Yang, Shi-Meng Zhou, Shao-Yu Guan, Liu-Kun Yang, Qi-Xin Shi, Ming-Gao Zhao, Qi Yang
Huntington's disease (HD) is an autosomal dominant inherited disease characterized by movement, psychiatric, and cognitive disorders. Previous research suggests that Praeruptorin C (Pra-C), an effective component in the root of Peucedanum praeruptorum dunn, a traditional Chinese medicine, may function in neuroprotection. The present study was conducted to evaluate the effectiveness of Pra-C in the treatment of HD-like symptoms in a 3-nitropropionic acid (3-NP) mouse model, and to explore the possible mechanism of the drug's activity...
December 7, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
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