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Huntingtin disease

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https://www.readbyqxmd.com/read/29341886/regulation-of-hsf1-protein-stabilization-an-updated-review
#1
REVIEW
Chao Huang, Jingjing Wu, Li Xu, Jili Wang, Zhuo Chen, Rongrong Yang
Heat shock factor 1 (HSF1) is a transcriptional factor that determines the efficiency of heat shock responses (HSRs) in the cell. Given its function has been extensively studied in recent years, HSF1 is considered a potential target for the treatment of disorders associated with protein aggregation. The activity of HSF1 is traditionally regulated at the transcriptional level in which the transactivation domain of HSF1 is modified by extensive array of pos-translational modifications, such as phosphorylation, sumoylation, and acetylation...
January 13, 2018: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29335600/alteration-in-fluidity-of-cell-plasma-membrane-in-huntington-disease-revealed-by-spectral-phasor-analysis
#2
Sara Sameni, Leonel Malacrida, Zhiqun Tan, Michelle A Digman
Huntington disease (HD) is a late-onset genetic neurodegenerative disorder caused by expansion of cytosine-adenine-guanine (CAG) trinucleotide in the exon 1 of the gene encoding the polyglutamine (polyQ). It has been shown that protein degradation and lipid metabolism is altered in HD. In many neurodegenerative disorders, impaired lipid homeostasis is one of the early events in the disease onset. Yet, little is known about how mutant huntingtin may affect phospholipids membrane fluidity. Here, we investigated how membrane fluidity in the living cells (differentiated PC12 and HEK293 cell lines) are affected using a hyperspectral imaging of widely used probes, LAURDAN...
January 15, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29328442/identification-of-differentially-expressed-genes-and-regulatory-relationships-in-huntington-s-disease-by-bioinformatics-analysis
#3
Xiaoyu Dong, Shuyan Cong
Huntington's disease (HD) is an inherited, progressive neurodegenerative disease caused by a CAG expansion in the huntingtin (HTT) gene; various dysfunctions of biological processes in HD have been proposed. However, at present the exact pathogenesis of HD is not fully understood. The present study aimed to explore the pathogenesis of HD using a computational bioinformatics analysis of gene expression. GSE11358 was downloaded from the Gene Expression Omnibus andthe differentially expressed genes (DEGs) in the mutant HTT knock‑in cell model STHdhQ111/Q111 were predicted...
January 9, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29324753/microrna-signatures-of-endogenous-huntingtin-cag-repeat-expansion-in-mice
#4
Peter Langfelder, Fuying Gao, Nan Wang, David Howland, Seung Kwak, Thomas F Vogt, Jeffrey S Aaronson, Jim Rosinski, Giovanni Coppola, Steve Horvath, X William Yang
In Huntington's disease (HD) patients and in model organisms, messenger RNA transcriptome has been extensively studied; in contrast, comparatively little is known about expression and potential role of microRNAs. Using RNA-sequencing, we have quantified microRNA expression in four brain regions and liver, at three different ages, from an allelic series of HD model mice with increasing CAG length in the endogenous Huntingtin gene. Our analyses reveal CAG length-dependent microRNA expression changes in brain, with 159 microRNAs selectively altered in striatum, 102 in cerebellum, 51 in hippocampus, and 45 in cortex...
2018: PloS One
https://www.readbyqxmd.com/read/29316776/phagocytic-roles-of-glial-cells-in-healthy-and-diseased-brains
#5
REVIEW
Yeon-Joo Jung, Won-Suk Chung
Glial cells are receiving much attention since they have been recognized as important regulators of many aspects of brain function and disease. Recent evidence has revealed that two different glial cells, astrocytes and microglia, control synapse elimination under normal and pathological conditions via phagocytosis. Astrocytes use the MEGF10 and MERTK phagocytic pathways, and microglia use the classical complement pathway to recognize and eliminate unwanted synapses. Notably, glial phagocytosis also contributes to the clearance of disease-specific protein aggregates, such as β-amyloid, huntingtin, and α-synuclein...
January 10, 2018: Biomolecules & Therapeutics
https://www.readbyqxmd.com/read/29311338/faulty-neuronal-determination-and-cell-polarization-are-reverted-by-modulating-hd-early-phenotypes
#6
P Conforti, D Besusso, V D Bocchi, A Faedo, E Cesana, G Rossetti, V Ranzani, C N Svendsen, L M Thompson, M Toselli, G Biella, M Pagani, E Cattaneo
Increasing evidence suggests that early neurodevelopmental defects in Huntington's disease (HD) patients could contribute to the later adult neurodegenerative phenotype. Here, by using HD-derived induced pluripotent stem cell lines, we report that early telencephalic induction and late neural identity are affected in cortical and striatal populations. We show that a large CAG expansion causes complete failure of the neuro-ectodermal acquisition, while cells carrying shorter CAGs repeats show gross abnormalities in neural rosette formation as well as disrupted cytoarchitecture in cortical organoids...
January 8, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29305855/microglia-derived-extracellular-vesicles-in-alzheimer-s-disease-a-double-edged-sword
#7
REVIEW
Teresa Trotta, Maria Antonietta Panaro, Antonia Cianciulli, Giorgio Mori, Adriana Di Benedetto, Chiara Porro
Extracellular vesicles (EVs), based on their origin or size, can be classified as apoptotic bodies, microvesicles (MVs)/microparticles (MPs), and exosomes. EVs are one of the new emerging modes of communication between cells that are providing new insights into the pathophysiology of several diseases. EVs released from activated or apoptotic cells contain specific proteins (signaling molecules, receptors, integrins, cytokines), bioactive lipids, nucleic acids (mRNA, miRNA, small non coding RNAs, DNA) from their progenitor cells...
January 3, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29302199/cell-to-cell-transmission-of-polyglutamine-aggregates-in-c-elegans
#8
Dong-Kyu Kim, Kyu-Won Cho, Woo Jung Ahn, Dayana Perez-Acuña, Hyunsu Jeong, He-Jin Lee, Seung-Jae Lee
Huntington disease (HD) is an inherited neurodegenerative disorder characterized by motor and cognitive dysfunction caused by expansion of polyglutamine (polyQ) repeat in exon 1 of huntingtin (HTT). In patients, the number of glutamine residues in polyQ tracts are over 35, and it is correlated with age of onset, severity, and disease progression. Expansion of polyQ increases the propensity for HTT protein aggregation, process known to be implicated in neurodegeneration. These pathological aggregates can be transmitted from neuron to another neuron, and this process may explain the pathological spreading of polyQ aggregates...
December 2017: Experimental Neurobiology
https://www.readbyqxmd.com/read/29297592/selected-health-and-lifestyle-factors-cytosine-adenine-guanine-status-and-phenoconversion-in-huntington-s-disease
#9
Caroline Tanner, Karen Marder, Shirley Eberly, Kevin Biglan, David Oakes, Ira Shoulson
BACKGROUND: In Huntington's disease, 60% of the variance in onset age is not explained by the huntingtin gene mutation. Huntington's disease onset was earlier in caffeine users. OBJECTIVE: The objective of this study was to assess the relationship of lifestyle factors with motor phenoconversion among persons at risk for Huntington's disease. METHODS: The associations of motor phenoconversion and exposure to selected lifestyle and health factors were examined using Cox proportional hazards analyses adjusted for age, gender, and repeat length...
January 3, 2018: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29288339/cdk5-contributes-to-huntington-s-disease-learning-and-memory-deficits-via-modulation-of-brain-region-specific-substrates
#10
Elena Alvarez-Periel, Mar Puigdellívol, Verónica Brito, Florian Plattner, James A Bibb, Jordi Alberch, Silvia Ginés
Cognitive deficits are a major hallmark of Huntington's disease (HD) with a great impact on the quality of patient's life. Gaining a better understanding of the molecular mechanisms underlying learning and memory impairments in HD is, therefore, of critical importance. Cdk5 is a proline-directed Ser/Thr kinase involved in the regulation of synaptic plasticity and memory processes that has been associated with several neurodegenerative disorders. In this study, we aim to investigate the role of Cdk5 in learning and memory impairments in HD using a novel animal model that expresses mutant huntingtin (mHtt) and has genetically reduced Cdk5 levels...
December 29, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/29282287/the-17-residue-long-n-terminus-in-huntingtin-controls-step-wise-aggregation-in-solution-and-on-membranes-via-different-mechanisms
#11
Nitin K Pandey, J Mario Isas, Anoop Rawat, Rachel V Lee, Jennifer Langen, Priyatama Pandey, Ralf Langen
Aggregation of huntingtin protein arising from expanded polyglutamine (polyQ) sequences in the exon-1 region of mutant huntingtin plays a central role in the pathogenesis of Huntington's disease. The huntingtin aggregation pathways are of therapeutic and diagnostic interest, but obtaining critical information from the physiologically relevant htt exon-1 (Httex1) protein has been challenging. Using biophysical techniques and an expression and purification protocol that generates clean, monomeric Httex1, we identified and mapped three distinct aggregation pathways: (1) unseeded in solution, (2) seeded in solution, and (3) membrane-mediated...
December 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29281014/systematic-genetic-interaction-studies-identify-histone-demethylase-utx-as-potential-target-for-ameliorating-huntington-s-disease
#12
Wan Song, Nóra Zsindely, Anikó Faragó, J Lawrence Marsh, László Bodai
Huntington's Disease (HD) is a dominantly inherited neurodegenerative disease caused by alterations in the huntingtin gene (htt). Transcriptional dysregulation is an early event in HD progression. Protein acetylation and methylation particularly on histones regulates chromatin structure thereby preventing or facilitating transcription. Although protein acetylation has been found to affect HD symptoms, little is known about the potential role of protein methylation in HD pathology. In recent years, a series of proteins have been described that are responsible for methylating and demethylating histones as well as other proteins...
December 21, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29259176/connecting-neuronal-cell-protective-pathways-and-drug-combinations-in-a-huntington-s-disease-model-through-the-application-of-quantitative-systems-pharmacology
#13
Fen Pei, Hongchun Li, Mark J Henderson, Steven A Titus, Ajit Jadhav, Anton Simeonov, Murat Can Cobanoglu, Seyed H Mousavi, Tongying Shun, Lee McDermott, Prema Iyer, Michael Fioravanti, Diane Carlisle, Robert M Friedlander, Ivet Bahar, D Lansing Taylor, Timothy R Lezon, Andrew M Stern, Mark E Schurdak
Quantitative Systems Pharmacology (QSP) is a drug discovery approach that integrates computational and experimental methods in an iterative way to gain a comprehensive, unbiased understanding of disease processes to inform effective therapeutic strategies. We report the implementation of QSP to Huntington's Disease, with the application of a chemogenomics platform to identify strategies to protect neuronal cells from mutant huntingtin induced death. Using the STHdh Q111 cell model, we investigated the protective effects of small molecule probes having diverse canonical modes-of-action to infer pathways of neuronal cell protection connected to drug mechanism...
December 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29259100/mglur5-antagonism-increases-autophagy-and-prevents-disease-progression-in-the-zq175-mouse-model-of-huntington-s-disease
#14
Khaled S Abd-Elrahman, Alison Hamilton, Shaunessy R Hutchinson, Fang Liu, Ryan C Russell, Stephen S G Ferguson
Huntington's disease (HD) is a neurodegenerative disease caused by an expansion in the huntingtin protein (also called Htt) that induces neuronal cell death with age. We found that the treatment of 12-month-old symptomatic heterozygous and homozygous zQ175 huntingtin knockin mice for 12 weeks with CTEP, a negative allosteric modulator of metabotropic glutamate receptor 5 (mGluR5), reduced the size and number of huntingtin aggregates, attenuated caspase-3 activity, and reduced both neuronal apoptosis and neuronal loss in brain tissue...
December 19, 2017: Science Signaling
https://www.readbyqxmd.com/read/29258536/down-regulation-of-mir-9-in-the-peripheral-leukocytes-of-huntington-s-disease-patients
#15
Kuo-Hsuan Chang, Yih-Ru Wu, Chiung-Mei Chen
BACKGROUND: Huntington's disease (HD), caused by expansion of a polyglutamine tract within HUNTINGTIN (HTT) protein, is an autosomal dominant neurodegenerative disease associated with a progressive neurodegeneration of striatum and cerebral cortex. Although a few studies have identified substantial microRNA (miRNA) alterations in central nervous tissues from HD patients, it will be more accessible to employ these molecular changes in peripheral tissues as biomarkers for HD. METHODS: We examined the expression levels of 13 miRNAs (miR-1, mirR-9, miR-9*, miR-10b, miR-29a, miR-29b, miR-124a, miR-132, miR-155, miR-196a, miR-196b, miR-330 and miR-615), 10 of which previously demonstrated alterations and 3 of which are potential regulators of differentially-expressed genes in brains of HD patients, in the peripheral leukocytes of 36 HD patients, 8 pre-symptomatic HD carriers and 28 healthy controls...
December 19, 2017: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/29234268/the-evidence-for-the-spread-and-seeding-capacities-of-the-mutant-huntingtin-protein-in-in-vitro-systems-and-their-therapeutic-implications
#16
REVIEW
Maria Masnata, Francesca Cicchetti
Neurodegenerative disorders are not only characterized by specific patterns of cell loss but the presence and accumulation of various pathological proteins-both of which correlate with disease evolution. There is now mounting evidence to suggest that these pathological proteins present with toxic, at times prion-like, properties and can therefore seed pathology in neighboring as well remotely connected healthy neurons as they spread across the brain. What is less clear, at this stage, is how much this actually contributes to, and drives, the core pathogenic events...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/29233555/human-neural-stem-cell-transplantation-rescues-functional-deficits-in-r6-2-and-q140-huntington-s-disease-mice
#17
Jack C Reidling, Aroa Relaño-Ginés, Sandra M Holley, Joseph Ochaba, Cindy Moore, Brian Fury, Alice Lau, Andrew H Tran, Sylvia Yeung, Delaram Salamati, Chunni Zhu, Asa Hatami, Carlos Cepeda, Joshua A Barry, Talia Kamdjou, Alvin King, Dane Coleal-Bergum, Nicholas R Franich, Frank M LaFerla, Joan S Steffan, Mathew Blurton-Jones, Charles K Meshul, Gerhard Bauer, Michael S Levine, Marie-Francoise Chesselet, Leslie M Thompson
Huntington's disease (HD) is an inherited neurodegenerative disorder with no disease-modifying treatment. Expansion of the glutamine-encoding repeat in the Huntingtin (HTT) gene causes broad effects that are a challenge for single treatment strategies. Strategies based on human stem cells offer a promising option. We evaluated efficacy of transplanting a good manufacturing practice (GMP)-grade human embryonic stem cell-derived neural stem cell (hNSC) line into striatum of HD modeled mice. In HD fragment model R6/2 mice, transplants improve motor deficits, rescue synaptic alterations, and are contacted by nerve terminals from mouse cells...
December 6, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/29232946/huntingtin-polyglutamine-dependent-protein-aggregation-in-reconstituted-cells
#18
Kodai Machida, Kuru Kanzawa, Tomoaki Shigeta, Yuki Yamamoto, Kanta Tsumoto, Hiroaki Imataka
One of the aims of synthetic biology is bottom-up construction of reconstituted human cells for medical uses. To that end, we generated giant unilamella vesicles (GUVs) that contained a HeLa cell extract, which comprises a cell-free protein synthesis (CFPS) system. Then we expressed Huntingtin protein fragments that contained polyglutamine (polyQ) sequences (Htt-polyQ), a hallmark of Huntington's disease. That system produced polyQ-dependent protein aggregates, as previously demonstrated in living cells. We next simplified the system by generating GUVs that contained purified human factors, which reconstituted a CFPS system...
December 12, 2017: ACS Synthetic Biology
https://www.readbyqxmd.com/read/29229845/brain-urea-increase-is-an-early-huntington-s-disease-pathogenic-event-observed-in-a-prodromal-transgenic-sheep-model-and-hd-cases
#19
Renee R Handley, Suzanne J Reid, Rudiger Brauning, Paul Maclean, Emily R Mears, Imche Fourie, Stefano Patassini, Garth J S Cooper, Skye R Rudiger, Clive J McLaughlan, Paul J Verma, James F Gusella, Marcy E MacDonald, Henry J Waldvogel, C Simon Bawden, Richard L M Faull, Russell G Snell
The neurodegenerative disorder Huntington's disease (HD) is typically characterized by extensive loss of striatal neurons and the midlife onset of debilitating and progressive chorea, dementia, and psychological disturbance. HD is caused by a CAG repeat expansion in the Huntingtin (HTT) gene, translating to an elongated glutamine tract in the huntingtin protein. The pathogenic mechanism resulting in cell dysfunction and death beyond the causative mutation is not well defined. To further delineate the early molecular events in HD, we performed RNA-sequencing (RNA-seq) on striatal tissue from a cohort of 5-y-old OVT73-line sheep expressing a human CAG-expansion HTT cDNA transgene...
December 26, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29225330/huntingtin-gene-repeat-size-variations-affect-risk-of-lifetime-depression
#20
REVIEW
Sarah L Gardiner, Martine J van Belzen, Merel W Boogaard, Willeke M C van Roon-Mom, Maarten P Rozing, Albert M van Hemert, Johannes H Smit, Aartjan T F Beekman, Gerard van Grootheest, Robert A Schoevers, Richard C Oude Voshaar, Raymund A C Roos, Hannie C Comijs, Brenda W J H Penninx, Roos C van der Mast, N Ahmad Aziz
Huntington disease (HD) is a severe neuropsychiatric disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion in the HTT gene. Although HD is frequently complicated by depression, it is still unknown to what extent common HTT CAG repeat size variations in the normal range could affect depression risk in the general population. Using binary logistic regression, we assessed the association between HTT CAG repeat size and depression risk in two well-characterized Dutch cohorts─the Netherlands Study of Depression and Anxiety and the Netherlands Study of Depression in Older Persons─including 2165 depressed and 1058 non-depressed persons...
December 11, 2017: Translational Psychiatry
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