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Huntingtin disease

Joseph Ochaba, Eva L Morozko, Jacqueline G O'Rourke, Leslie M Thompson
The accumulation of misfolded proteins is central to pathology in Huntington's disease (HD) and many other neurodegenerative disorders. Specifically, a key pathological feature of HD is the aberrant accumulation of mutant HTT (mHTT) protein into high molecular weight complexes and intracellular inclusion bodies composed of fragments and other proteins. Conventional methods to measure and understand the contributions of various forms of mHTT-containing aggregates include fluorescence microscopy, western blot analysis, and filter trap assays...
February 27, 2018: Journal of Visualized Experiments: JoVE
Chye Soi Moi, Chia Kin Yen, Khuen Yen Ng, Koh Rhun Yian
Protein misfolding and aggregation have been considered the common pathological hallmarks for a number of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). These abnormal proteins aggregation damage mitochondria and induce oxidative stress and resulting neuronal cell death. Prolong neuronal damage activates microglia and astrocytes, development of inflammation reaction and further promotes neurodegeneration. Thus, elimination of abnormal proteins aggregation without eliciting any adverse effects are the main treatment strategies...
March 15, 2018: CNS & Neurological Disorders Drug Targets
Magdalena Dabrowska, Wojciech Juzwa, Wlodzimierz J Krzyzosiak, Marta Olejniczak
Huntington's disease (HD) is a progressive autosomal dominant neurodegenerative disorder caused by the expansion of CAG repeats in the first exon of the huntingtin gene ( HTT ). The accumulation of polyglutamine-rich huntingtin proteins affects various cellular functions and causes selective degeneration of neurons in the striatum. Therapeutic strategies used to date to silence the expression of mutant HTT include antisense oligonucleotides, RNA interference-based approaches and, recently, genome editing with the CRISPR/Cas9 system...
2018: Frontiers in Neuroscience
Laurie Galvan, Laetitia Francelle, Marie-Claude Gaillard, Lucie de Longprez, Maria-Angeles Carrillo-de Sauvage, Géraldine Liot, Karine Cambon, Lev Stimmer, Sophie Luccantoni, Julien Flament, Julien Valette, Michel de Chaldée, Gwenaelle Auregan, Martine Guillermier, Charlène Joséphine, Fanny Petit, Caroline Jan, Margot Jarrige, Noëlle Dufour, Gilles Bonvento, Sandrine Humbert, Frédéric Saudou, Philippe Hantraye, Karine Merienne, Alexis-Pierre Bemelmans, Anselme L Perrier, Nicole Déglon, Emmanuel Brouillet
The neurobiological functions of a number of kinases expressed in the brain are unknown. Here, we report new findings on DCLK3 (doublecortin like kinase 3), which is preferentially expressed in neurons in the striatum and dentate gyrus. Its function has never been investigated. DCLK3 expression is markedly reduced in Huntington's disease. Recent data obtained in studies related to cancer suggest DCLK3 could have an anti-apoptotic effect. Thus, we hypothesized that early loss of DCLK3 in Huntington's disease may render striatal neurons more susceptible to mutant huntingtin (mHtt)...
March 9, 2018: Brain: a Journal of Neurology
Priscila A C Valadão, Matheus P S M Gomes, Bárbara C Aragão, Hermann A Rodrigues, Jéssica N Andrade, Rubens Garcias, Julliane V Joviano-Santos, Murilo A Luiz, Wallace L Camargo, Lígia A Naves, Christopher Kushmerick, Walter L G Cavalcante, Márcia Gallacci, Itamar C G de Jesus, Silvia Guatimosim, Cristina Guatimosim
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterized by chorea, incoordination, and psychiatric and behavioral symptoms. The leading cause of death in HD patients is aspiration pneumonia, associated with respiratory dysfunction, decreased respiratory muscle strength and dysphagia. Although most of the motor symptoms are derived from alterations in the central nervous system, some might be associated with changes in the components of motor units (MU). To explore this hypothesis, we evaluated morphofunctional aspects of the diaphragm muscle in a mouse model of HD (BACHD)...
March 9, 2018: Neurochemistry International
Marco Caterino, Tiziana Squillaro, Daniela Montesarchio, Antonio Giordano, Concetta Giancola, Mariarosa A B Melone
Huntington's disease is a dreadful, incurable disorder. It springs from the autosomal dominant mutation in the first exon of the HTT gene, which encodes for the huntingtin protein (HTT) and results in progressive neurodegeneration. Thus far, all the attempted approaches to tackle the mutant HTT-induced toxicity causing this disease have failed. The mutant protein comes with the aberrantly expanded poly-glutamine tract. It is primarily to blame for the build-up of β-amyloid-like HTT aggregates, deleterious once broadened beyond the critical ∼35-37 repeats threshold...
March 8, 2018: Neuropharmacology
N Cabezas-Llobet, L Vidal-Sancho, M Masana, A Fournier, J Alberch, D Vaudry, X Xifró
Deficits in hippocampal synaptic plasticity result in cognitive impairment in Huntington's disease (HD). Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that exerts neuroprotective actions, mainly through the PAC1 receptor. However, the role of PACAP in cognition is poorly understood, and no data exists in the context of Huntington's disease (HD). Here, we investigated the ability of PACAP receptor stimulation to enhance memory development in HD. First, we observed a hippocampal decline of all three PACAP receptor expressions, i...
March 10, 2018: Molecular Neurobiology
Dagmar E Ehrnhoefer, Dale D O Martin, Mandi E Schmidt, Xiaofan Qiu, Safia Ladha, Nicholas S Caron, Niels H Skotte, Yen T N Nguyen, Kuljeet Vaid, Amber L Southwell, Sabine Engemann, Sonia Franciosi, Michael R Hayden
Huntington disease (HD) is caused by the expression of mutant huntingtin (mHTT) bearing a polyglutamine expansion. In HD, mHTT accumulation is accompanied by a dysfunction in basal autophagy, which manifests as specific defects in cargo loading during selective autophagy. Here we show that the expression of mHTT resistant to proteolysis at the caspase cleavage site D586 (C6R mHTT) increases autophagy, which may be due to its increased binding to the autophagy adapter p62. This is accompanied by faster degradation of C6R mHTT in vitro and a lack of mHTT accumulation the C6R mouse model with age...
March 6, 2018: Acta Neuropathologica Communications
Silvia Corrochano, Gonzalo Blanco, Debbie Williams, Jessica Wettstein, Michelle Simon, Saumya Kumar, Lee Moir, Thomas Agnew, Michelle Stewart, Allison Landman, Vassilios N Kotiadis, Michael R Duchen, Henning Wackerhage, David C Rubinsztein, Steve D M Brown, Abraham Acevedo-Arozena
Polyglutamine expansions in the huntingtin gene cause Huntington's disease (HD). Huntingtin is ubiquitously expressed, leading to pathological alterations also in peripheral organs. Variations in the length of the polyglutamine tract explain up to 70% of the age-at-onset variance, with the rest of the variance attributed to genetic and environmental modifiers. To identify novel disease modifiers, we performed an unbiased mutagenesis screen on an HD mouse model, identifying a mutation in the skeletal muscle voltage-gated sodium channel (Scn4a, termed 'draggen' mutation) as a novel disease enhancer...
March 2, 2018: Human Molecular Genetics
Frank Matthes, Serena Massari, Anna Bochicchio, Kenji Schorpp, Judith Schilling, Stephanie Weber, Nina Offermann, Jenny Desantis, Erich E Wanker, Paolo Carloni, Kamyar Hadian, Oriana Tabarrini, Giulia Rossetti, Sybille Krau Szlig
Expanded CAG trinucleotide repeats in Huntington's disease (HD) are causative for neurotoxicity. Not only does the mutant CAG-repeat RNA encode for neurotoxic polyglutamine proteins, but also it can lead to a toxic gain-of-function by aberrantly recruiting RNA-binding proteins. One of these is the MID1 protein, which induces aberrant Huntingtin (HTT) protein translation upon binding. Here we have identified a set of CAG repeat binder candidates by in silico methods. One of those, furamidine, reduces the binding of HTT mRNA to MID1 and other target proteins in vitro...
March 5, 2018: ACS Chemical Neuroscience
Jana Miniarikova, Melvin M Evers, Pavlina Konstantinova
The single mutation underlying the fatal neuropathology of Huntington's disease (HD) is a CAG triplet expansion in exon 1 of the huntingtin (HTT) gene, which gives rise to a toxic mutant HTT protein. There have been a number of not yet successful therapeutic advances in the treatment of HD. The current excitement in the HD field is due to the recent development of therapies targeting the culprit of HD either at the DNA or RNA level to reduce the overall mutant HTT protein. In this review, we briefly describe short-term and long-term HTT-lowering strategies targeting HTT transcripts...
February 8, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Antonella Cardinale, Francesca R Fusco
Huntington's disease (HD) is a fatal neurodegenerative condition, due to a mutation in the IT15 gene encoding for huntingtin. Currently, disease-modifying therapy is not available for HD, and only symptomatic drugs are administered for the management of symptoms. In the last few years, preclinical and clinical studies have indicated that pharmacological strategies aimed at inhibiting cyclic nucleotide phosphodiesterase (PDEs) may develop into a novel therapeutic approach in neurodegenerative disorders. PDEs are a family of enzymes that hydrolyze cyclic nucleotides into monophosphate isoforms...
March 3, 2018: CNS Neuroscience & Therapeutics
Olivia Monteiro, Changwei Chen, Ryan Bingham, Argyrides Argyrou, Rachel Buxton, Christina Pancevac Jönsson, Emma Jones, Angela Bridges, Kelly Gatfield, Sybille Krauß, Jeremy Lambert, Rosamund Langston, Susann Schweiger, Iain Uings
Expression of mutant Huntingtin (HTT) protein is central to the pathophysiology of Huntington's Disease (HD). The E3 ubiquitin ligase MID1 appears to have a key role in facilitating translation of the mutant HTT mRNA suggesting that interference with the function of this complex could be an attractive therapeutic approach. Here we describe a peptide that is able to disrupt the interaction between MID1 and the α4 protein, a regulatory subunit of protein phosphatase 2A (PP2A). By fusing this peptide to a sequence from the HIV-TAT protein we demonstrate that the peptide can disrupt the interaction within cells and show that this results in a decrease in levels of ribosomal S6 phosphorylation and HTT expression in cultures of cerebellar granule neurones derived from HdhQ111/Q7 mice...
February 27, 2018: Neuroscience Letters
L J McMeekin, Y Li, S N Fox, G C Rowe, D K Crossman, J J Day, Y Li, P J Detloff, R M Cowell
Multiple lines of evidence indicate that a reduction in the expression and function of the transcriptional coactivator peroxisome proliferator activated receptor gamma coactivator-1α (PGC-1α) is associated with neurodegeneration in diseases such as Huntington Disease (HD). Polymorphisms in the PGC-1α gene modify HD progression, and PGC-1α expression is reduced in striatal medium spiny neurons (MSNs) of HD patients and mouse models. However, neither the MSN-specific function of PGC-1α nor the contribution of PGC-1α deficiency to motor dysfunction is known...
February 28, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Zhe Qu, Santosh R D'Mello
A defining feature of neurodegenerative diseases is the abnormal and excessive loss of neurons. One molecule that is particularly important in promoting neuronal death in a variety of cell culture and in vivo models of neurodegeneration is histone deacetylase-3 (HDAC3), a member of the histone deacetylase family of proteins. As a step towards understanding how HDAC3 promotes neuronal death, we conducted a proteomic screen aimed at identifying proteins that were regulated by HDAC3. HDAC3 was overexpressed in cultured rat cerebellar granule neurons (CGNs) and protein lysates were analyzed by mass spectrometry...
January 1, 2018: Experimental Biology and Medicine
Eris Bidollari, Giovannina Rotundo, Daniela Ferrari, Ornella Candido, Laura Bernardini, Federica Consoli, Alessandro De Luca, Iolanda Santimone, Giuseppe Lamorte, Andrea Ilari, Ferdinando Squitieri, Angelo Luigi Vescovi, Jessica Rosati
Huntington's disease (HD) is an incurable, autosomal dominant, hereditary neurodegenerative disorder that typically manifests itself in midlife. This pathology is linked to the deregulation of multiple, as yet unknown, cellular processes starting before HD onset. A human iPS cell line was generated from skin fibroblasts of a subject at the presymptomatic life stage, carrying a polyglutamine expansion in HTT gene codifying Huntingtin protein. The iPSC line contained the expected CAG expansion, expressed the expected pluripotency markers, displayed in vivo differentiation potential to the three germ layers and had a normal karyotype...
February 21, 2018: Stem Cell Research
Jun Wu, Daniel Ryskamp, Lutz Birnbaumer, Ilya Bezprozvanny
BACKGROUND: Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. We previously discovered that mutant Huntingtin sensitizes type 1 inositol 1,4,5-trisphosphate receptor (InsP3R1) to InsP3. This causes calcium leakage from the endoplasmic reticulum (ER) and a compensatory increase in neuronal store-operated calcium (nSOC) entry. We previously demonstrated that supranormal nSOC leads to synaptic loss in striatal medium spiny neurons (MSNs) in YAC128 HD mice...
2018: Journal of Huntington's Disease
Qiang Guo, Bin Huang, Jingdong Cheng, Manuel Seefelder, Tatjana Engler, Günter Pfeifer, Patrick Oeckl, Markus Otto, Franziska Moser, Melanie Maurer, Alexander Pautsch, Wolfgang Baumeister, Rubén Fernández-Busnadiego, Stefan Kochanek
Huntingtin (HTT) is a large (348 kDa) protein that is essential for embryonic development and is involved in diverse cellular activities such as vesicular transport, endocytosis, autophagy and the regulation of transcription. Although an integrative understanding of the biological functions of HTT is lacking, the large number of identified HTT interactors suggests that it serves as a protein-protein interaction hub. Furthermore, Huntington's disease is caused by a mutation in the HTT gene, resulting in a pathogenic expansion of a polyglutamine repeat at the amino terminus of HTT...
February 21, 2018: Nature
Xiao Zhou, Gang Li, Anna Kaplan, Michael M Gaschler, Xiaoyan Zhang, Zhipeng Hou, Jiang Mali, Roseann Zott, Serge Cremers, Brent R Stockwell, Wenzhen Duan
Huntington's disease (HD) is caused by a cytosine-adenine-guanine (CAG) trinucleotide repeat expansion in the huntingtin (HTT) gene encoding an elongated polyglutamine tract within the N-terminal of the Huntingtin protein (Htt) and leads to Htt misfolding, aberrant protein aggregation, and progressive appearance of disease symptoms. Chronic activation of endoplasmic reticulum (ER) stress by mutant Htt (mHtt) results in cellular dysfunction and ultimately cell death. Protein disulfide isomerase (PDI) is a chaperone protein located in the ER...
February 16, 2018: Human Molecular Genetics
Jordi Creus-Muncunill, Laura Rué, Rafael Alcalá-Vida, Raquel Badillos-Rodríguez, Joan Romaní-Aumedes, Sonia Marco, Jordi Alberch, Isabel Perez-Otaño, Cristina Malagelada, Esther Pérez-Navarro
Rictor associates with mTOR to form the mTORC2 complex, which activity regulates neuronal function and survival. Neurodegenerative diseases are characterized by the presence of neuronal dysfunction and cell death in specific brain regions such as for example Huntington's disease (HD), which is characterized by the loss of striatal projection neurons leading to motor dysfunction. Although HD is caused by the expression of mutant huntingtin, cell death occurs gradually suggesting that neurons have the capability to activate compensatory mechanisms to deal with neuronal dysfunction and later cell death...
February 19, 2018: Molecular Neurobiology
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