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https://www.readbyqxmd.com/read/28213125/reduced-bioavailable-manganese-causes-striatal-urea-cycle-pathology-in-huntington-s-disease-mouse-model
#1
Terry Jo V Bichell, Michal Wegrzynowicz, K Grace Tipps, Emma M Bradley, Michael A Uhouse, Miles Bryan, Kyle Horning, Nicole Fisher, Karrie Dudek, Timothy Halbesma, Preethi Umashanker, Andrew D Stubbs, Hunter K Holt, Gunnar F Kwakye, Andrew M Tidball, Roger J Colbran, Michael Aschner, M Diana Neely, Alba Di Pardo, Vittorio Maglione, Alexander Osmand, Aaron B Bowman
Huntington's disease (HD) is caused by a mutation in the huntingtin gene (HTT), resulting in profound striatal neurodegeneration through an unknown mechanism. Perturbations in the urea cycle have been reported in HD models and in HD patient blood and brain. In neurons, arginase is a central urea cycle enzyme, and the metal manganese (Mn) is an essential cofactor. Deficient biological responses to Mn, and reduced Mn accumulation have been observed in HD striatal mouse and cell models. Here we report in vivo and ex vivo evidence of a urea cycle metabolic phenotype in a prodromal HD mouse model...
February 14, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28211815/generation-and-characterization-of-knock-in-mouse-models-expressing-versions-of-huntingtin-with-either-an-n17-or-a-combined-polyq-and-proline-rich-region-deletion
#2
Emily A André, Elise M Braatz, Jeh-Ping Liu, Scott O Zeitlin
BACKGROUND: The polyglutamine (polyQ) stretch of the Huntingtin protein (HTT) in mammals is flanked by a highly conserved 17 amino acid N-terminal domain (N17), and a proline-rich region (PRR). The PRR is a binding site for many HTT-interacting proteins, and the N17 domain regulates several normal HTT functions, including HTT's ability to associate with membranes and organelles. OBJECTIVE: This study investigates the consequence of deleting mouse Huntingtin's (Htt's) N17 domain or a combination of its polyQ stretch and PRR (QP) on normal Htt function in mice...
February 16, 2017: Journal of Huntington's Disease
https://www.readbyqxmd.com/read/28194132/molecular-imaging-markers-to-track-huntington-s-disease-pathology
#3
REVIEW
Heather Wilson, Rosa De Micco, Flavia Niccolini, Marios Politis
Huntington's disease (HD) is a progressive, monogenic dominant neurodegenerative disorder caused by repeat expansion mutation in the huntingtin gene. The accumulation of mutant huntingtin protein, forming intranuclear inclusions, subsequently leads to degeneration of medium spiny neurons in the striatum and cortical areas. Genetic testing can identify HD gene carriers before individuals develop overt cognitive, psychiatric, and chorea symptoms. Thus, HD gene carriers can be studied in premanifest stages to understand and track the evolution of HD pathology...
2017: Frontiers in Neurology
https://www.readbyqxmd.com/read/28182673/the-expanded-cag-repeat-in-the-huntingtin-gene-as-target-for-therapeutic-rna-modulation-throughout-the-hd-mouse-brain
#4
Nicole A Datson, Anchel González-Barriga, Eleni Kourkouta, Rudie Weij, Jeroen van de Giessen, Susan Mulders, Outi Kontkanen, Taneli Heikkinen, Kimmo Lehtimäki, Judith C T van Deutekom
The aim of these studies was to demonstrate the therapeutic capacity of an antisense oligonucleotide with the sequence (CUG)7 targeting the expanded CAG repeat in huntingtin (HTT) mRNA in vivo in the R6/2 N-terminal fragment and Q175 knock-in Huntington's disease (HD) mouse models. In a first study, R6/2 mice received six weekly intracerebroventricular infusions with a low and high dose of (CUG)7 and were sacrificed 2 weeks later. A 15-60% reduction of both soluble and aggregated mutant HTT protein was observed in striatum, hippocampus and cortex of (CUG)7-treated mice...
2017: PloS One
https://www.readbyqxmd.com/read/28175299/inhibiting-sphingosine-kinase-2-mitigates-mutant-huntingtin-induced-neurodegeneration-in-neuron-models-of-huntington-disease
#5
Jose F Moruno-Manchon, Ndidi-Ese Uzor, Maria P Blasco, Sishira Mannuru, Nagireddy Putluri, Erin E Furr-Stimming, Andrey S Tsvetkov
No abstract text is available yet for this article.
February 8, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28153533/dysregulation-of-gene-expression-in-the-striatum-of-bachd-rats-expressing-full-length-mutant-huntingtin-and-associated-abnormalities-on-molecular-and-protein-levels
#6
Libo Yu-Taeger, Michael Bonin, Janice Stricker-Shaver, Olaf Riess, Hoa Huu Phuc Nguyen
Huntington disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in the gene coding for the huntingtin protein (HTT). Mutant HTT (mHTT) has been proposed to cause neuronal dysfunction and neuronal loss through multiple mechanisms. Transcriptional changes may be a core pathogenic feature of HD. Utilizing the Affymetrix platform we performed a genome-wide RNA expression analysis in two BACHD transgenic rat lines (TG5 and TG9) at 12 months of age, both of which carry full-length human mHTT but with different expression levels...
January 30, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28137862/dyrk1a-regulates-hap1-dcaf7-wdr68-binding-with-implication-for-delayed-growth-in-down-syndrome
#7
Jianxing Xiang, Su Yang, Ning Xin, Marta A Gaertig, Roger H Reeves, Shihua Li, Xiao-Jiang Li
Huntingtin-associated protein 1 (Hap1) is known to be critical for postnatal hypothalamic function and growth. Hap1 forms stigmoid bodies (SBs), unique neuronal cytoplasmic inclusions of unknown function that are enriched in hypothalamic neurons. Here we developed a simple strategy to isolate the SB-enriched fraction from mouse brain. By analyzing Hap1 immunoprecipitants from this fraction, we identified a Hap1-interacting SB component, DDB1 and CUL4 associated factor 7 (Dcaf7)/WD40 repeat 68 (WDR68), whose protein level and nuclear translocation are regulated by Hap1...
January 30, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28132929/identification-of-brain-substrates-of-transglutaminase-by-functional-proteomics-supports-its-role-in-neurodegenerative-diseases
#8
William André, Isabelle Nondier, Maud Valensi, François Guillonneau, Christian Federici, Guylaine Hoffner, Philippe Djian
Transglutaminases are calcium-dependent enzymes that catalyze the formation of ε-(γ-glutamyl)lysine isopeptide bonds between specific glutamine and lysine residues. Some transglutaminase isoforms are present in the brain and are thought to participate in the protein aggregation characteristic of neurological diseases such as Huntington, Alzheimer's and Parkinson's disease. We have developed a functional proteomics strategy in which biotinylated amine-donor and amine-acceptor probes were used to identify the transglutaminase substrates present in brain...
January 26, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28129919/loss-of-huntingtin-stimulates-capture-of-retrograde-dense-core-vesicles-to-increase-synaptic-neuropeptide-stores
#9
Dinara Bulgari, David L Deitcher, Edwin S Levitan
The Huntington's disease protein Huntingtin (Htt) regulates axonal transport of dense-core vesicles (DCVs) containing neurotrophins and neuropeptides. DCVs travel down axons to reach nerve terminals where they are either captured in synaptic boutons to support later release or reverse direction to reenter the axon as part of vesicle circulation. Currently, the impact of Htt on DCV dynamics in the terminal is unknown. Here we report that knockout of Drosophila Htt selectively reduces retrograde DCV flux at proximal boutons of motoneuron terminals...
January 22, 2017: European Journal of Cell Biology
https://www.readbyqxmd.com/read/28129107/crispr-cas9-editing-of-the-mutant-huntingtin-allele-in%C3%A2-vitro-and-in%C3%A2-vivo
#10
Alex Mas Monteys, Shauna A Ebanks, Megan S Keiser, Beverly L Davidson
Huntington disease (HD) is a fatal dominantly inherited neurodegenerative disorder caused by CAG repeat expansion (>36 repeats) within the first exon of the huntingtin gene. Although mutant huntingtin (mHTT) is ubiquitously expressed, the brain shows robust and early degeneration. Current RNA interference-based approaches for lowering mHTT expression have been efficacious in mouse models, but basal mutant protein levels are still detected. To fully mitigate expression from the mutant allele, we hypothesize that allele-specific genome editing can occur via prevalent promoter-resident SNPs in heterozygosity with the mutant allele...
January 4, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28123081/histone-deacetylase-inhibitors-protect-against-pyruvate-dehydrogenase-dysfunction-in-huntington-s-disease
#11
Luana Naia, Teresa Cunha-Oliveira, Joana Rodrigues, Tatiana R Rosenstock, Ana Oliveira, Márcio Ribeiro, Catarina Carmo, Sofia I Oliveira-Sousa, Ana I Duarte, Michael R Hayden, A Cristina Rego
: Transcriptional deregulation and changes in mitochondrial bioenergetics, including pyruvate dehydrogenase (PDH) dysfunction, have been described in Huntington's disease (HD). We previously showed that histone deacetylase inhibitors (HDACi), trichostatin A and sodium butyrate (SB), ameliorate mitochondrial function in cells expressing mutant huntingtin. In this work we investigated the effect of HDACi on regulation of PDH activity in striatal cells derived from HD knock-in mice and YAC128 mice...
January 25, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28111121/risk-factors-for-the-onset-and-progression-of-huntington-disease
#12
Ting-Kuang Chao, Jing Hu, Tamara Pringsheim
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by chorea, behavioural and psychiatric manifestations, and dementia, caused by a CAG triplet repeat expansion in the huntingtin gene. Systematic review of the literature was conducted to determine the risk factors for the onset and progression of HD. Multiple databases were searched, using terms specific to Huntington disease and to studies of aetiology, risk, prevention and genetics, limited to studies on human subjects published in English or French between 1950 and 2010...
January 20, 2017: Neurotoxicology
https://www.readbyqxmd.com/read/28104789/a-novel-humanized-mouse-model-of-huntington-disease-for-preclinical-development-of-therapeutics-targeting-mutant-huntingtin-alleles
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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