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https://www.readbyqxmd.com/read/28424652/quantitative-electroencephalographic-biomarkers-in-preclinical-and-human-studies-of-huntington-s-disease-are-they-fit-for-purpose-for-treatment-development
#1
REVIEW
Michael K Leuchter, Elissa J Donzis, Carlos Cepeda, Aimee M Hunter, Ana María Estrada-Sánchez, Ian A Cook, Michael S Levine, Andrew F Leuchter
A major focus in development of novel therapies for Huntington's disease (HD) is identification of treatments that reduce the burden of mutant huntingtin (mHTT) protein in the brain. In order to identify and test the efficacy of such therapies, it is essential to have biomarkers that are sensitive to the effects of mHTT on brain function to determine whether the intervention has been effective at preventing toxicity in target brain systems before onset of clinical symptoms. Ideally, such biomarkers should have a plausible physiologic basis for detecting the effects of mHTT, be measureable both in preclinical models and human studies, be practical to measure serially in clinical trials, and be reliably measurable in HD gene expansion carriers (HDGECs), among other features...
2017: Frontiers in Neurology
https://www.readbyqxmd.com/read/28424476/neurons-export-extracellular-vesicles-enriched-in-cysteine-string-protein-and-misfolded-protein-cargo
#2
Jingti Deng, Carolina Koutras, Julien Donnelier, Mana Alshehri, Maryam Fotouhi, Martine Girard, Steve Casha, Peter S McPherson, Stephen M Robbins, Janice E A Braun
The fidelity of synaptic transmission depends on the integrity of the protein machinery at the synapse. Unfolded synaptic proteins undergo refolding or degradation in order to maintain synaptic proteostasis and preserve synaptic function, and buildup of unfolded/toxic proteins leads to neuronal dysfunction. Many molecular chaperones contribute to proteostasis, but one in particular, cysteine string protein (CSPα), is critical for proteostasis at the synapse. In this study we report that exported vesicles from neurons contain CSPα...
April 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28413881/molecular-mechanism-on-stabilizing-huntingtin-n17-helical-structure-in-micelle-environment
#3
Leili Zhang, Hongsuk Kang, Francisco X Vázquez, Leticia Marisel Toledo-Sherman, Binquan Luan, Ruhong Zhou
Huntington's disease is a deadly neurodegenerative disease caused by the fibrilization of huntingtin (HTT) exon-1 protein mutants. Despite extensive efforts over the past decade, much remains unknown about the structures of (mutant) HTT exon-1 and their enigmatic roles in aggregation. Particularly, whether the first 17 residues in the N-terminal (HTT-N17) adopt a helical or a coiled structure remains unclear. Here, with the rigorous study of molecular dynamics simulations, we explored the most possible structures of HTT-N17 in both dodecylphosphocholine (DPC) micelles and aqueous solution, using three commonly applied force fields (OPLS-AA/L, CHARMM36 and AMBER99sb*-ILDNP) to examine the underlying molecular mechanism and rule out the potential artifacts...
April 17, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28406926/high-resolution-respirometry-of-fine-needle-muscle-biopsies-in-pre-manifest-huntington-s-disease-expansion-mutation-carriers-shows-normal-mitochondrial-respiratory-function
#4
Eva Buck, Martina Zügel, Uwe Schumann, Tamara Merz, Anja M Gumpp, Anke Witting, Jürgen M Steinacker, G Bernhard Landwehrmeyer, Patrick Weydt, Enrico Calzia, Katrin S Lindenberg
Alterations in mitochondrial respiration are an important hallmark of Huntington's disease (HD), one of the most common monogenetic causes of neurodegeneration. The ubiquitous expression of the disease causing mutant huntingtin gene raises the prospect that mitochondrial respiratory deficits can be detected in skeletal muscle. While this tissue is readily accessible in humans, transgenic animal models offer the opportunity to cross-validate findings and allow for comparisons across organs, including the brain...
2017: PloS One
https://www.readbyqxmd.com/read/28406616/inhibition-of-huntingtin-exon-1-aggregation-by-the-molecular-tweezer-clr01
#5
Tobias Vöpel, Kenny Bravo-Rodriguez, Sumit Mittal, Shivang Vachharajani, David Gnutt, Abhishek Sharma, Anne Steinhof, Oluwaseun Fatoba, Gisa Ellrichmann, Michael Nshanian, Christian Heid, Joseph A Loo, Frank-Gerrit Klärner, Thomas Schrader, Gal Bitan, Erich E Wanker, Simon Ebbinghaus, Elsa Sanchez-Garcia
Huntington's disease is a neurodegenerative disorder associated with the expansion of the polyglutamine tract in the exon-1 domain of the huntingtin protein (htt(e1)). Above a threshold of 37 glutamine residues, htt(e1) starts to aggregate in a nucleation-dependent manner. A 17-residue N-terminal fragment of htt(e1) (N17) has been suggested to play a crucial role in modulating the aggregation propensity and toxicity of htt(e1). Here we identify N17 as a potential target for novel therapeutic intervention using the molecular tweezer CLR01...
April 13, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28406522/inhibition-of-polyglutamine-aggregation-by-similar-huntingtin-n-terminal-sequences-prospective-molecules-for-preclinical-evaluation-in-huntington-s-disease
#6
Gunasekhar Burra, Ashwani Kumar Thakur
The mutant huntingtin protein (mHtt) fragments with expanded polyglutamine sequence forms microscopically visible aggregates in neurons, a hallmark of Huntington's disease (HD). The aggregation process and aggregates are possible targets of therapeutic intervention in HD. Due to lack of treatment and cure, the patients die within 15-20 years after the disease onset. Therefore, discovering therapeutic molecules that may either inhibit the aggregation mechanism or downregulate the toxic effects of mhtt are highly needed...
April 12, 2017: Biopolymers
https://www.readbyqxmd.com/read/28400517/aggregation-landscapes-of-huntingtin-exon-1-protein-fragments-and-the-critical-repeat-length-for-the-onset-of-huntington-s-disease
#7
Mingchen Chen, Peter G Wolynes
Huntington's disease (HD) is a neurodegenerative disease caused by an abnormal expansion in the polyglutamine (polyQ) track of the Huntingtin (HTT) protein. The severity of the disease depends on the polyQ repeat length, arising only in patients with proteins having 36 repeats or more. Previous studies have shown that the aggregation of N-terminal fragments (encoded by HTT exon 1) underlies the disease pathology in mouse models and that the HTT exon 1 gene product can self-assemble into amyloid structures. Here, we provide detailed structural mechanisms for aggregation of several protein fragments encoded by HTT exon 1 by using the associative memory, water-mediated, structure and energy model (AWSEM) to construct their free energy landscapes...
April 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28398721/the-inclusions-of-r6-2-mice-are-not-amyloid-and-differ-structurally-from-those-of-huntington-disease-brain
#8
William André, Christophe Sandt, Isabelle Nondier, Philippe Djian, Guylaine Hoffner
R6/2 mice contain an N-terminal fragment of human huntingtin with an expanded polyQ and develop a neurological disease resembling Huntington disease. Although the brain of R6/2 mice contains numerous inclusions, there is very little neuronal death. In that respect, R6/2 mice differ from patients with Huntington disease whose striatum and cerebral cortex develop inclusions associated with extensive neuronal loss. We have previously demonstrated using synchrotron-based infrared microspectroscopy that the striatum and the cortex of patients with Huntington disease contained inclusions specifically enriched in amyloid β-sheets...
April 11, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28396959/glucose-transportation-in-the-brain-and-its-impairment-in-huntington-disease-one-more-shade-of-the-energetic-metabolism-failure
#9
REVIEW
Veronica Morea, Eris Bidollari, Gianni Colotti, Annarita Fiorillo, Jessica Rosati, Lidia De Filippis, Ferdinando Squitieri, Andrea Ilari
Huntington's disease (HD) or Huntington's chorea is the most common inherited, dominantly transmitted, neurodegenerative disorder. It is caused by increased CAG repeats number in the gene coding for huntingtin (Htt) and characterized by motor, behaviour and psychiatric symptoms, ultimately leading to death. HD patients also exhibit alterations in glucose and energetic metabolism, which result in pronounced weight loss despite sustained calorie intake. Glucose metabolism decreases in the striatum of all the subjects with mutated Htt, but affects symptom presentation only when it drops below a specific threshold...
April 10, 2017: Amino Acids
https://www.readbyqxmd.com/read/28396396/formation-of-neurodegenerative-aggresome-and-death-inducing-signaling-complex-in-maternal-diabetes-induced-neural-tube-defects
#10
Zhiyong Zhao, Lixue Cao, E Albert Reece
Diabetes mellitus in early pregnancy increases the risk in infants of birth defects, such as neural tube defects (NTDs), known as diabetic embryopathy. NTDs are associated with hyperglycemia-induced protein misfolding and Caspase-8-induced programmed cell death. The present study shows that misfolded proteins are ubiquitinylated, suggesting that ubiquitin-proteasomal degradation is impaired. Misfolded proteins form aggregates containing ubiquitin-binding protein p62, suggesting that autophagic-lysosomal clearance is insufficient...
April 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28391067/n-type-ca-2-channels-are-affected-by-full-length-mutant-huntingtin-expression-in-a-mouse-model-of-huntington-s-disease
#11
Flavia R Silva, Artur S Miranda, Rebeca P M Santos, Isabella G Olmo, Gerald W Zamponi, Tomas Dobransky, Jader S Cruz, Luciene B Vieira, Fabiola M Ribeiro
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the amino-terminal region of the huntingtin (htt) protein. In addition to facilitating neurodegeneration, mutant htt is implicated in HD-related alterations of neurotransmission. Previous data showed that htt can modulate N-type voltage-gated Ca(2+) channels (Cav2.2), which are essential for presynaptic neurotransmitter release. Thus, to elucidate the mechanism underlying mutant htt-mediated alterations in neurotransmission, we investigated how Cav2...
March 18, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28391013/p35-hemizygosity-activates-akt-but-does-not-improve-motor-function-in-the-yac128-mouse-model-of-huntington-s-disease
#12
Kevin H J Park, Sonia Franciosi, Kristina Parrant, Ge Lu, Blair R Leavitt
Huntington's disease (HD) is a hereditary neurodegenerative disorder resulting from N-terminal polyglutamine expansion in the huntingtin protein. A relatively selective and early loss of medium spiny neurons in the striatum is a hallmark of HD neuropathology. Although the exact mechanism of mutant huntingtin-mediated neurodegeneration is unclear, recent evidence suggests that NMDA-receptor-mediated excitotoxicity is involved. Our previously published findings show that decreasing levels of the cdk5 activators, p35 and p25, reduces NMDA receptor-mediated excitotoxicity in striatal neurons in vivo...
April 6, 2017: Neuroscience
https://www.readbyqxmd.com/read/28384479/mutant-huntingtin-disrupts-the-nuclear-pore-complex
#13
Jonathan C Grima, J Gavin Daigle, Nicolas Arbez, Kathleen C Cunningham, Ke Zhang, Joseph Ochaba, Charlene Geater, Eva Morozko, Jennifer Stocksdale, Jenna C Glatzer, Jacqueline T Pham, Ishrat Ahmed, Qi Peng, Harsh Wadhwa, Olga Pletnikova, Juan C Troncoso, Wenzhen Duan, Solomon H Snyder, Laura P W Ranum, Leslie M Thompson, Thomas E Lloyd, Christopher A Ross, Jeffrey D Rothstein
Huntington's disease (HD) is caused by an expanded CAG repeat in the Huntingtin (HTT) gene. The mechanism(s) by which mutant HTT (mHTT) causes disease is unclear. Nucleocytoplasmic transport, the trafficking of macromolecules between the nucleus and cytoplasm, is tightly regulated by nuclear pore complexes (NPCs) made up of nucleoporins (NUPs). Previous studies offered clues that mHTT may disrupt nucleocytoplasmic transport and a mutation of an NUP can cause HD-like pathology. Therefore, we evaluated the NPC and nucleocytoplasmic transport in multiple models of HD, including mouse and fly models, neurons transfected with mHTT, HD iPSC-derived neurons, and human HD brain regions...
April 5, 2017: Neuron
https://www.readbyqxmd.com/read/28384474/polyglutamine-expanded-huntingtin-exacerbates-age-related-disruption-of-nuclear-integrity-and-nucleocytoplasmic-transport
#14
Fatima Gasset-Rosa, Carlos Chillon-Marinas, Alexander Goginashvili, Ranjit Singh Atwal, Jonathan W Artates, Ricardos Tabet, Vanessa C Wheeler, Anne G Bang, Don W Cleveland, Clotilde Lagier-Tourenne
Onset of neurodegenerative disorders, including Huntington's disease, is strongly influenced by aging. Hallmarks of aged cells include compromised nuclear envelope integrity, impaired nucleocytoplasmic transport, and accumulation of DNA double-strand breaks. We show that mutant huntingtin markedly accelerates all of these cellular phenotypes in a dose- and age-dependent manner in cortex and striatum of mice. Huntingtin-linked polyglutamine initially accumulates in nuclei, leading to disruption of nuclear envelope architecture, partial sequestration of factors essential for nucleocytoplasmic transport (Gle1 and RanGAP1), and intranuclear accumulation of mRNA...
April 5, 2017: Neuron
https://www.readbyqxmd.com/read/28377290/synaptopathic-mechanisms-of-neurodegeneration-and-dementia-insights-from-huntington-s-disease
#15
REVIEW
Shiraz Tyebji, Anthony J Hannan
Dementia encapsulates a set of symptoms that include loss of mental abilities such as memory, problem solving or language, and reduces a person's ability to perform daily activities. Alzheimer's disease is the most common form of dementia, however dementia can also occur in other neurological disorders such as Huntington's disease (HD). Many studies have demonstrated that loss of neuronal cell function manifests pre-symptomatically and thus is a relevant therapeutic target to alleviate symptoms. Synaptopathy, the physiological dysfunction of synapses, is now being approached as the target for many neurological and psychiatric disorders, including HD...
April 1, 2017: Progress in Neurobiology
https://www.readbyqxmd.com/read/28368337/crispr-cas9-mediated-gene-silencing-of-the-mutant-huntingtin-gene-in-an-in-vitro-model-of-huntington-s-disease
#16
Nivya Kolli, Ming Lu, Panchanan Maiti, Julien Rossignol, Gray L Dunbar
Huntington's disease (HD) is a fatal neurodegenerative genetic disease characterized by a loss of neurons in the striatum. It is caused by a mutation in the Huntingtin gene (HTT) that codes for the protein huntingtin (HTT). The mutant Huntingtin gene (mHTT) contains extra poly-glutamine (CAG) repeats from which the translated mutant huntingtin proteins (mHTT) undergo inappropriate post-translational modifications, conferring a toxic gain of function, in addition to its non-functional property. In order to curb the production of the mHTT, we have constructed two CRISPR (clustered regularly interspaced short palindromic repeat)-Cas9 (CRISPR associate protein) plasmids, among which one nicks the DNA at untranslated region upstream to the open reading frame (uORF), and the other nicks the DNA at exon1-intron boundary...
April 2, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28359739/2-4-dnp-improves-motor-function-preserves-medium-spiny-neuronal-identity-and-reduces-oxidative-stress-in-a-mouse-model-of-huntington-s-disease
#17
Bin Wu, Mali Jiang, Qi Peng, Gang Li, Zhipeng Hou, Ginger L Milne, Susumu Mori, Robert Alonso, John G Geisler, Wenzhen Duan
Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the first exon of the gene huntingtin. There is no treatment to prevent or delay the disease course of HD currently. Oxidative stress and mitochondrial dysfunction have emerged as key determinants of the disease progression in HD. Therefore, counteracting mutant huntingtin (mHtt)-induced oxidative stress and mitochondrial dysfunction appears as a new approach to treat this devastating disease. Interestingly, mild mitochondrial uncoupling improves neuronal resistance to stress and facilitates neuronal survival...
March 28, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28356891/variable-effects-of-autophagy-induction-by-trehalose-on-herpesviruses-depending-on-conditions-of-infection
#18
Jeffery L Meier, Charles Grose
Trehalose is a non-reducing sugar formed from two glucose units. Trehalose induces abundant autophagy in cultured cells and also reduces the rate of aggregation of the huntingtin protein in the animal model of Huntington disease, a chronic neurological disease in humans. The mechanism of this effect on autophagy is now known to be caused by starvation secondary to inhibition of a family of glucose transporters known as the solute carrier 2 or the glucose transporter family. Variable effects of trehalose treatment have been observed during infections with two herpesviruses-human cytomegalovirus and varicella-zoster virus...
March 2017: Yale Journal of Biology and Medicine
https://www.readbyqxmd.com/read/28339401/is-huntingtin-dispensable-in-the-adult-brain
#19
Jeh-Ping Liu, Scott O Zeitlin
Huntingtin (HTT) is an essential protein during early embryogenesis and the development of the central nervous system (CNS). Conditional knock-out of mouse Huntingtin (Htt) expression in the CNS beginning during neural development, as well as reducing Htt expression only during embryonic and early postnatal stages, results in neurodegeneration in the adult brain. These findings suggest that HTT is important for the development and/or maintenance of the CNS, but they do not address the question of whether HTT is required specifically in the adult CNS for its normal functions and/or homeostasis...
2017: Journal of Huntington's Disease
https://www.readbyqxmd.com/read/28339398/n-terminal-fragments-of-huntingtin-longer-than-residue-170-form-visible-aggregates-independently-to-polyglutamine-expansion
#20
Moore Z Chen, Sue-Ann Mok, Angelique R Ormsby, Paul J Muchowski, Danny M Hatters
BACKGROUND: A hallmark of Huntington's disease is the progressive aggregation of full length and N-terminal fragments of polyglutamine (polyQ)-expanded Huntingtin (Htt) into intracellular inclusions. The production of N-terminal fragments appears important for enabling pathology and aggregation; and hence the direct expression of a variety of N-terminal fragments are commonly used to model HD in animal and cellular models. OBJECTIVE: It remains unclear how the length of the N-terminal fragments relates to polyQ - mediated aggregation...
2017: Journal of Huntington's Disease
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