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https://www.readbyqxmd.com/read/28100843/pathophysiology-and-molecular-basis-of-selected-metabolic-abnormalities-in-huntington-s-disease
#1
Jolanta Krzysztoń-Russjan
Huntington's disease (HD) is an incurable, devastating neurodegenerative disease with a known genetic background and autosomally dominant inheritance pattern. HTT gene mutation (mHTT) is associated with polymorphic fragment elongation above 35 repeats of the CAG triplet. The mHTT product is an altered protein with a poly-Q elongated fragment, with the highest expression determined in the central nervous system (CNS) and with differentiated expression outside the CNS. A drastic loss of striatal and deeper layers of the cerebral cortex neurons was determined in the CNS, but muscle and body weight mass loss with dysfunction of many organs was also observed...
December 30, 2016: Postȩpy Higieny i Medycyny Doświadczalnej
https://www.readbyqxmd.com/read/28096245/prion-like-characteristics-of-polyglutamine-containing-proteins
#2
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/28075185/cerebellar-heterogeneity-and-its-impact-on-pet-data-quantification-of-5-ht-receptor-radioligands
#3
Melanie Ganz, Ling Feng, Hanne Demant Hansen, Vincent Beliveau, Claus Svarer, Gitte M Knudsen, Douglas N Greve
In the quantification of positron emission tomography (PET) radiotracer binding, a commonly used method is reference tissue modeling (RTM). RTM necessitates a proper reference and a ubiquitous choice for G-protein coupled receptors is the cerebellum. We investigated regional differences in uptake within the grey matter of the cerebellar hemispheres (CH), the cerebellar white matter (CW), and the cerebellar vermis (CV) for five PET radioligands targeting the serotonin system. Furthermore, we evaluated the impact of choosing different reference regions when quantifying neocortical binding...
January 1, 2017: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/28054945/somatic-genetic-variation-in-solid-pseudopapillary-tumor-of-the-pancreas-by-whole-exome-sequencing
#4
Meng Guo, Guopei Luo, Kaizhou Jin, Jiang Long, He Cheng, Yu Lu, Zhengshi Wang, Chao Yang, Jin Xu, Quanxing Ni, Xianjun Yu, Chen Liu
Solid pseudopapillary tumor of the pancreas (SPT) is a rare pancreatic disease with a unique clinical manifestation. Although CTNNB1 gene mutations had been universally reported, genetic variation profiles of SPT are largely unidentified. We conducted whole exome sequencing in nine SPT patients to probe the SPT-specific insertions and deletions (indels) and single nucleotide polymorphisms (SNPs). In total, 54 SNPs and 41 indels of prominent variations were demonstrated through parallel exome sequencing. We detected that CTNNB1 mutations presented throughout all patients studied (100%), and a higher count of SNPs was particularly detected in patients with older age, larger tumor, and metastatic disease...
January 3, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28053035/a-high-resolution-in-vivo-atlas-of-the-human-brain-s-serotonin-system
#5
Vincent Beliveau, Melanie Ganz, Ling Feng, Brice Ozenne, Liselotte Højgaard, Patrick M Fisher, Claus Svarer, Douglas N Greve, Gitte M Knudsen
: The serotonin (5-hydroxytryptamine, 5-HT) system modulates many important brain functions and is critically involved in many neuropsychiatric disorders. Here, we present a high-resolution, multidimensional, in vivo atlas of four of the human brain's 5-HT receptors (5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4) and the 5-HT transporter (5-HTT). The atlas is created from molecular and structural high-resolution neuroimaging data consisting of positron emission tomography (PET) and magnetic resonance imaging (MRI) scans acquired in a total of 210 healthy individuals...
January 4, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28032313/development-of-research-on-huntington-disease-in-china
#6
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
#7
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/28017473/huntingtin-mediated-multipolar-bipolar-transition-of-newborn-cortical-neurons-is-critical-for-their-postnatal-neuronal-morphology
#8
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/28000697/the-targetable-a1-huntington-disease-haplotype-has-distinct-amerindian-and-european-origins-in-latin-america
#9
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/27988204/smad-transcription-factors-are-altered-in-cell-models-of-hd-and-regulate-htt-expression
#10
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/27979358/dna-repair-in-the-trinucleotide-repeat-disorders
#11
Lesley Jones, Henry Houlden, Sarah J Tabrizi
BACKGROUND: Inherited diseases caused by unstable repeated DNA sequences are rare, but together represent a substantial cause of morbidity. Trinucleotide repeat disorders are severe, usually life-shortening, neurological disorders caused by nucleotide expansions, and most have no disease-modifying treatments. Longer repeat expansions are associated with genetic anticipation (ie, earlier disease onset in successive generations), although the differences in age at onset are not entirely accounted for by repeat length...
January 2017: Lancet Neurology
https://www.readbyqxmd.com/read/27957784/d-cycloserine-enhanced-extinction-of-cocaine-induced-conditioned-place-preference-is-attenuated-in-serotonin-transporter-knockout-rats
#12
Peter Karel, Francesca Calabrese, Marco Riva, Paola Brivio, Bas Van der Veen, Liesbeth Reneman, Michel Verheij, Judith Homberg
d-Cycloserine (DCS), a partial NMDA receptor agonist, has been proposed as a cognitive enhancer to facilitate the extinction of drug-related memories. However, it is unknown whether there are individual differences in the efficacy of DCS. Here, we set out to investigate the influence of serotonin transporter (5-HTT) genotype on DCS treatment outcome and the underlying neural mechanism. To that end, we first determined the mRNA levels of several NMDA receptor subunits and observed a reduction in NR1/NR2C receptors in the ventromedial prefrontal cortex and nucleus accumbens of 5-HTT(-/-) compared with 5-HTT(+/+) rats...
December 12, 2016: Addiction Biology
https://www.readbyqxmd.com/read/27957684/huntingtin-polyq-mutation-impairs-the-17%C3%AE-estradiol-neuroglobin-pathway-devoted-to-neuron-survival
#13
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/27941843/whole-genome-sequencing-of-eight-goat-populations-for-the-detection-of-selection-signatures-underlying-production-and-adaptive-traits
#14
Xiaolong Wang, Jing Liu, Guangxian Zhou, Jiazhong Guo, Hailong Yan, Yiyuan Niu, Yan Li, Chao Yuan, Rongqing Geng, Xianyong Lan, Xiaopeng An, Xingui Tian, Huangkai Zhou, Jiuzhou Song, Yu Jiang, Yulin Chen
The goat (Capra hircus) is one of the first farm animals that have undergone domestication and extensive natural and artificial selection by adapting to various environments, which in turn has resulted in its high level of phenotypic diversity. Here, we generated medium-coverage (9-13×) sequences from eight domesticated goat breeds, representing morphologically or geographically specific populations, to identify genomic regions representing selection signatures. We discovered ~10 million single nucleotide polymorphisms (SNPs) for each breed...
December 12, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27938392/ulk1-mediated-phosphorylation-of-atg14-promotes-autophagy-and-is-impaired-in-huntington-s-disease-models
#15
Mitchell S Wold, Junghyun Lim, Véronik Lachance, Zhiqiang Deng, Zhenyu Yue
BACKGROUND: Autophagy is a bulk degradation pathway for long-lived proteins, protein aggregates, and damaged organelles. ULK1 protein kinase and Vps34 lipid kinase are two key autophagy regulators that are critical for autophagosome biogenesis. However, it isn't fully understood how ULK1 regulates Vps34, especially in the context of disease. Polyglutamine expansion in huntingtin (Htt) causes aberrant accumulation of the aggregated protein and disrupts various cellular pathways including autophagy, a lysosomal degradation pathway, underlying the pathogenesis of Huntington's disease (HD)...
December 9, 2016: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/27934595/generation-of-human-embryonic-stem-cell-line-chhes-458-from-abnormal-embryos-with-htt-gene-mutation
#16
Pingyuan Xie, Yanfang Sun, Xiaoying Zhou, Jing Chen, Juan Du, Yi Sun, Guangxiu Lu, Ge Lin, Qi Ouyang
The human embryonic stem cell (hESC) line chHES-458 was derived from a abnormal blastocyst carrying the expanded CAG repeat mutation of the HTT gene that would lead to Huntington disease. This cell line maintained a normal karyotype 46, XX during long-term culture and displayed pluripotent characteristics, including expression of pluripotency-related transcription factors and capacity of forming well-differentiated three germ layers after being injected into the SCID mice.
November 5, 2016: Stem Cell Research
https://www.readbyqxmd.com/read/27933583/looking-beyond-the-5-httlpr-polymorphism-genetic-and-epigenetic-layers-of-regulation-affecting-the-serotonin-transporter-gene-expression
#17
REVIEW
Sandra Iurescia, Davide Seripa, Monica Rinaldi
Serotonin (5-HT) is a neurotransmitter that regulates fundamental aspects of brain development, physiology and behaviour. The serotonin transporter (5-HTT) is deputized to the reuptake of 5-HT from the intersynaptic space in the presynaptic neurons. 5-HTT governs duration and magnitude of 5-HT biological actions, acting as a master regulator of the fine-tuning of 5-HT signalling. Genetic variation at SLC6A4 gene locus, encoding 5-HTT, contributes to alteration in 5-HT reuptake. The 5-HTTLPR/rs25531/rs25532 polymorphisms located in the promoter region of SLC6A4 gene have been associated with stress-related psychopathology and functional brain phenotypes...
December 8, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27924526/the-p-r151c-polymorphism-in-mc1r-gene-modifies-the-age-of-onset-in-spanish-huntington-s-disease-patients
#18
Gemma Tell-Marti, Joan Anton Puig-Butille, Pol Gimenez-Xavier, Ariadna Segu-Roig, Miriam Potrony, Celia Badenas, Victoria Alvarez, José M Millán, María José Trujillo-Tiebas, María A Ramos-Arroyo, Montserrat Milà, Susana Puig
The expansion of CAG repeats (≥36 CAG) in the HTT gene is the only known genetic cause of Huntington's disease (HD) and the main determinant of the course of the disease. The length of the expanded CAG repeats correlates inversely with the age of onset (AOO) but does not completely determine it. We investigated the role of the melanocortin 1 receptor (MC1R) gene as a modifier factor of AOO in 600 HD patients from Spain. We sequenced the entire region of the MC1R gene and analyzed all the nonsynonymous MC1R genetic variants with a minor allele frequency of at least 0...
December 6, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27913616/genetic-contributors-to-intergenerational-cag-repeat-instability-in-huntington-s-disease-knock-in-mice
#19
João Luís Neto, Jong-Min Lee, Ali Afridi, Tammy Gillis, Jolene R Guide, Stephani Dempsey, Brenda Lager, Isabel Alonso, Vanessa C Wheeler, Ricardo Mouro Pinto
Huntington's disease is a neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in exon 1 of the HTT gene. Longer repeat sizes are associated with increased disease penetrance and earlier ages of onset. Intergenerationally unstable transmissions are common in Huntington's disease families, partly underlying the genetic anticipation seen in this disorder. Huntington's disease CAG knock-in mouse models also exhibit a propensity for intergenerational repeat size changes. In this work, we examine intergenerational instability of the CAG repeat in over 20,000 transmissions in the largest Huntington's disease knock-in mouse model breeding datasets reported to date...
December 2, 2016: Genetics
https://www.readbyqxmd.com/read/27900343/divergence-and-rewiring-of-regulatory-networks-for-neural-development-between-human-and-other-species
#20
COMMENT
Ping Wang, Dejian Zhao, Shira Rockowitz, Deyou Zheng
Neural and brain development in human and other mammalian species are largely similar, but distinct features exist at the levels of macrostructure and underlying genetic control. Comparative studies of epigenetic regulation and transcription factor (TF) binding in humans, chimpanzees, rodents, and other species have found large differences in gene regulatory networks. A recent analysis of the cistromes of REST/NRSF, a critical transcriptional regulator for the nervous system, demonstrated that REST binding to syntenic genomic regions (i...
2016: Neurogenesis (Austin, Tex.)
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