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Huntingtin disease

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https://www.readbyqxmd.com/read/29134957/hunting-for-the-mutant-without-the-map-k
#1
Leon Tejwani, Janghoo Lim
In a paper recently published in Cell Research, Yu et al. identify two MAPK-related kinases, MAPK11 and HIPK3, as positive regulators of levels of mutant huntingtin protein, a toxic species highly involved in Huntington's disease (HD) pathology. The identification and validation of these kinases as therapeutic targets for knockdown in multiple relevant experimental model systems reveal novel potential approaches for treatment of HD.
November 14, 2017: Cell Research
https://www.readbyqxmd.com/read/29134321/co-occurrence-of-mixed-proteinopathies-in-late-stage-huntington-s-disease
#2
Isabelle St-Amour, Andréanne Turgeon, Claudia Goupil, Emmanuel Planel, Sébastien S Hébert
Accumulating evidence highlights the potential role of mixed proteinopathies (i.e., abnormal protein aggregation) in the development of clinical manifestations of neurodegenerative diseases (NDD). Huntington's disease (HD) is an inherited NDD caused by autosomal-dominant expanded CAG trinucleotide repeat mutation in the gene coding for Huntingtin (Htt). Previous studies have suggested the coexistence of phosphorylated-Tau, α-synuclein (α-Syn) and TAR DNA-binding protein 43 (TDP-43) inclusions in HD. However, definite evidence that HD pathology in humans can be accompanied by other proteinopathies is still lacking...
November 13, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/29125493/validation-of-ultrasensitive-mutant-huntingtin-detection-in-human-cerebrospinal-fluid-by-single-molecule-counting-immunoassay
#3
Valentina Fodale, Roberto Boggio, Manuel Daldin, Cristina Cariulo, Maria Carolina Spiezia, Lauren Mary Byrne, Blair R Leavitt, Edward Wild, Douglas Macdonald, Andreas Weiss, Alberto Bresciani
BACKGROUND: The measurement of disease-relevant biomarkers has become a major component of clinical trial design, but in the absence of rigorous clinical and analytical validation of detection methodology, interpretation of results may be misleading. In Huntington's disease (HD), measurement of the concentration of mutant huntingtin protein (mHTT) in cerebrospinal fluid (CSF) of patients may serve as both a disease progression biomarker and a pharmacodynamic readout for HTT-lowering therapeutic approaches...
November 9, 2017: Journal of Huntington's Disease
https://www.readbyqxmd.com/read/29125492/towards-an-understanding-of-energy-impairment-in-huntington-s-disease-brain
#4
Janet M Dubinsky
This review systematically examines the evidence for shifts in flux through energy generating biochemical pathways in Huntington's disease (HD) brains from humans and model systems. Compromise of the electron transport chain (ETC) appears not to be the primary or earliest metabolic change in HD pathogenesis. Rather, compromise of glucose uptake facilitates glucose flux through glycolysis and may possibly decrease flux through the pentose phosphate pathway (PPP), limiting subsequent NADPH and GSH production needed for antioxidant protection...
November 9, 2017: Journal of Huntington's Disease
https://www.readbyqxmd.com/read/29121340/hace1-is-essential-for-astrocyte-mitochondrial-function-and-influences-huntington-disease-phenotypes-in-vivo
#5
Dagmar E Ehrnhoefer, Amber L Southwell, Meenalochani Sivasubramanian, Xiaofan Qiu, Erika B Villanueva, Yuanyun Xie, Sabine Waltl, Lisa Anderson, Anita Fazeli, Lorenzo Casal, Boguslaw Felczak, Michelle Tsang, Michael R Hayden
Oxidative stress is a prominent feature of Huntington disease (HD), and we have shown previously that reduced levels of HACE1 (HECT domain and Ankyrin repeat containing E3 ubiquitin protein ligase 1) in patient striatum may contribute to the pathogenesis of HD. HACE1 promotes the stability of Nrf2 and thus plays an important role in antioxidant response mechanisms, which are dysfunctional in HD. Moreover, HACE1 overexpression mitigates mutant huntingtin-induced oxidative stress in vitro through promotion of the Nrf2 antioxidant response...
November 7, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29115989/clusterin-protects-neurons-against-intracellular-proteotoxicity
#6
Jenna M Gregory, Daniel R Whiten, Rebecca A Brown, Teresa P Barros, Janet R Kumita, Justin J Yerbury, Sandeep Satapathy, Karina McDade, Colin Smith, Leila M Luheshi, Christopher M Dobson, Mark R Wilson
It is now widely accepted in the field that the normally secreted chaperone clusterin is redirected to the cytosol during endoplasmic reticulum (ER) stress, although the physiological function(s) of this physical relocation remain unknown. We have examined in this study whether or not increased expression of clusterin is able to protect neuronal cells against intracellular protein aggregation and cytotoxicity, characteristics that are strongly implicated in a range of neurodegenerative diseases. We used the amyotrophic lateral sclerosis-associated protein TDP-43 as a primary model to investigate the effects of clusterin on protein aggregation and neurotoxicity in complementary in vitro, neuronal cell and Drosophila systems...
November 7, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29104136/nucleic-acid-aptamers-for-neurodegenerative-diseases
#7
REVIEW
Alix Bouvier-Müller, Frédéric Ducongé
The increased incidence of neurodegenerative diseases represents a huge challenge for societies. These diseases are characterized by neuronal death and include several different pathologies, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease and transmissible spongiform encephalopathies. Most of these pathologies are often associated with the aggregation of misfolded proteins, such as amyloid-ß, tau, α-synuclein, huntingtin and prion proteins. However, the precise mechanisms that lead to neuronal dysfunction and death in these diseases remain poorly understood...
November 2, 2017: Biochimie
https://www.readbyqxmd.com/read/29101592/localization-of-neuroglobin-in-the-brain-of-r6-2-mouse-model-of-huntington-s-disease
#8
A Cardinale, F R Fusco, E Paldino, C Giampà, M Marino, M T Nuzzo, V D'Angelo, D Laurenti, G Straccia, D Fasano, D Sarnataro, T Squillaro, S Paladino, Mariarosa A B Melone
Neuroglobin (Ngb) is expressed in the central and peripheral nervous system, cerebrospinal fluid, retina, and endocrine tissues where it is involved in binding O2 and other gasotransmitters. Several studies have highlighted its endogenous neuroprotective function. Huntington's disease (HD), a dominant hereditary disease, is characterized by the gradual loss of neurons in discrete areas of the central nervous system. We analyzed the expression of Ngb in the brain tissue of a mouse model of HD, in order to define the role of Ngb with respect to individual cell type vulnerability in HD and to gender and age of mice...
November 3, 2017: Neurological Sciences
https://www.readbyqxmd.com/read/29093475/hsp90-recognizes-the-n-terminus-of-huntingtin-involved-in-regulation-of-huntingtin-aggregation-by-usp19
#9
Wen-Tian He, Wei Xue, Yong-Guang Gao, Jun-Ye Hong, Hong-Wei Yue, Lei-Lei Jiang, Hong-Yu Hu
Huntington's disease (HD) is caused by aberrant expansion of polyglutamine (polyQ) in the N-terminus of huntingtin (Htt). Our previous study has demonstrated that HSP90 is involved in the triage decision of Htt, but how HSP90 recognizes and regulates Htt remains elusive. We investigated the interaction between HSP90 and the N-terminal fragments of Htt (Htt-N), such as the N-terminal 90-residue fragment (Htt-N90). Our results showed that HSP90 binds to the N-terminal extreme of Htt-N in a sequence just ahead of the polyQ tract...
November 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29089980/promises-and-pitfalls-of-immune-based-strategies-for-huntington-s-disease
#10
REVIEW
Gabriela Delevati Colpo, Erin Furr Stimming, Natalia Pessoa Rocha, Antonio Lucio Teixeira
Huntington's disease (HD) is an autosomal-dominant neurodegenerative disease characterized by the selective loss of neurons in the striatum and cortex, leading to progressive motor dysfunction, cognitive decline and behavioral symptoms. HD is caused by a trinucleotide (CAG) repeat expansion in the gene encoding for huntingtin. Several studies have suggested that inflammation is an important feature of HD and it is already observed in the early stages of the disease. Recently, new molecules presenting anti-inflammatory and/or immunomodulatory have been investigated for HD...
September 2017: Neural Regeneration Research
https://www.readbyqxmd.com/read/29069396/presence-of-tau-pathology-within-foetal-neural-allografts-in-patients-with-huntington-s-and-parkinson-s-disease
#11
Giulia Cisbani, Alexander Maxan, Jeffrey H Kordower, Emmanuel Planel, Thomas B Freeman, Francesca Cicchetti
Cell replacement has been explored as a therapeutic strategy to repair the brain in patients with Huntington's and Parkinson's disease. Post-mortem evaluations of healthy grafted tissue in such cases have revealed the development of Huntington- or Parkinson-like pathology including mutant huntingtin aggregates and Lewy bodies. An outstanding question remains if tau pathology can also be seen in patients with Huntington's and Parkinson's disease who had received foetal neural allografts. This was addressed by immunohistochemical/immunofluorescent stainings performed on grafted tissue of two Huntington's disease patients, who came to autopsy 9 and 12 years post-transplantation, and two patients with Parkinson's disease who came to autopsy 18 months and 16 years post-transplantation...
November 1, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29068569/role-of-thiamine-in-huntington-s-disease-pathogenesis-in-vitro-studies
#12
Beata M Gruber-Bzura, Jolanta Krzysztoń-Russjan, Irena Bubko, Jarosław Syska, Małgorzata Jaworska, Adam Zmysłowski, Magdalena Rosłon, Janina Drozd, Ewa Drozd, Edyta Majorczyk, Elżbieta L Anuszewska
BACKGROUND: Oxidative stress accompanies neurodegeneration and also causes abnormalities in thiaminedependent processes. These processes have been reported to be diminished in the brains of patients with several neurodegenerative diseases. OBJECTIVES: The aim of this work was to conduct a comparative analysis of the impact of supplemented thiamine on the viability of human B lymphocytes with CAG abnormal expanded huntingtin gene (mHTT) (GM13509) and control, B lymphocytes without mHTT (GM14467) through the following studies: determination of the supplemented thiamine concentrations, which are effective for cell growth stimulation after incubation in thiamine deficit conditions; determination of cell capability to intake the exogenous thiamine; evaluation of exogenous thiamine influence on the profile of the genes related to thiamine and energy metabolism; determination of ATP synthesis and activities of thiamine-dependent enzymes, KGDHC and BCKDHC in the intact cells and upon the exogenous thiamine...
August 2017: Advances in Clinical and Experimental Medicine: Official Organ Wroclaw Medical University
https://www.readbyqxmd.com/read/29066943/optimization-of-trans-splicing-for-huntington-s-disease-rna-therapy
#13
Hansjörg Rindt, Colton M Tom, Christian L Lorson, Virginia B Mattis
Huntington's disease (HD) is a devastating neurodegenerative disorder caused by a polyglutamine (polyQ) expansion in exon 1 of the Huntingtin (HTT) gene. We have previously demonstrated that spliceosome-mediated trans-splicing is a viable molecular strategy to specifically reduce and repair mutant HTT (mtHTT). Here, the targeted tethering efficacy of the pre-mRNA trans-splicing modules (PTM) in HTT was optimized. Various PTMs that targeted the 3' end of HTT intron 1 or the intron 1 branch point were shown trans-splice into an HTT mini-gene, as well as the endogenous HTT pre-mRNA...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/29056363/pramipexole-reduces-soluble-mutant-huntingtin-and-protects-striatal-neurons-through-dopamine-d3-receptors-in-a-genetic-model-of-huntington-s-disease
#14
Diego Luis-Ravelo, Héctor Estévez-Silva, Pedro Barroso-Chinea, Domingo Afonso-Oramas, Josmar Salas-Hernández, Julia Rodríguez-Núñez, Abraham Acevedo-Arozena, Daniel Marcellino, Tomás González-Hernández
Huntington's disease (HD) is a neurodegenerative disorder caused by abnormal expansion of the polyglutamine tract in the huntingtin protein (HTT). The toxicity of mutant HTT (mHTT) is associated with intermediate mHTT soluble oligomers that subsequently form intranuclear inclusions. Thus, interventions promoting the clearance of soluble mHTT are regarded as neuroprotective. Striatal neurons are particularly vulnerable in HD. Their degeneration underlies motor symptoms and striatal atrophy, the anatomical hallmark of HD...
October 19, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/29037056/-neuroacanthocytosis-diagnosis-with-new-generation-whole-exome-sequencing
#15
Kinga Hadzsiev, Mónika Szőts, Anett Fekete, László Balikó, Kim Boycott, Ferenc Nagy, Béla Melegh
In a patient with marked symptoms of Huntington disease after the huntingtin testing, which gave normal result, a whole exome sequencing (WES) has been performed based on an international collaboration. A homozygous G>A nucleotid change in the exon 34 of the VPS13A gene has been detected with WES, a mutation resulting in a premature stop codon at the position 1301. This change is a known pathogenic mutation. The aim of this article is to draw attention on the importance of the WES in the diagnosis of rare neurological diseases without any specific symptoms...
October 2017: Orvosi Hetilap
https://www.readbyqxmd.com/read/29036832/neuropathological-comparison-of-adult-onset-and-juvenile-huntington-s-disease-with-cerebellar-atrophy-a-report-of%C3%A2-a%C3%A2-father-and-son
#16
Caitlin S Latimer, Margaret E Flanagan, Patrick J Cimino, Suman Jayadev, Marie Davis, Zachary S Hoffer, Thomas J Montine, Luis F Gonzalez-Cuyar, Thomas D Bird, C Dirk Keene
BACKGROUND: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a trinucleotide (CAG) repeat expansion in huntingtin (HTT) on chromosome 4. Anticipation can cause longer repeat expansions in children of HD patients. Juvenile Huntington's disease (JHD), defined as HD arising before age 20, accounts for 5-10% of HD cases, with cases arising in the first decade accounting for approximately 1%. Clinically, JHD differs from the predominately choreiform adult onset Huntington's disease (AOHD) with variable presentations, including symptoms such as myoclonus, seizures, Parkinsonism, and cognitive decline...
October 11, 2017: Journal of Huntington's Disease
https://www.readbyqxmd.com/read/29033132/assembly-and-function-of-heterotypic-ubiquitin-chains-in-cell-cycle-and-protein-quality-control
#17
Richard G Yau, Kerstin Doerner, Erick R Castellanos, Diane L Haakonsen, Achim Werner, Nan Wang, X William Yang, Nadia Martinez-Martin, Marissa L Matsumoto, Vishva M Dixit, Michael Rape
Posttranslational modification with ubiquitin chains controls cell fate in all eukaryotes. Depending on the connectivity between subunits, different ubiquitin chain types trigger distinct outputs, as seen with K48- and K63-linked conjugates that drive protein degradation or complex assembly, respectively. Recent biochemical analyses also suggested roles for mixed or branched ubiquitin chains, yet without a method to monitor endogenous conjugates, the physiological significance of heterotypic polymers remained poorly understood...
November 2, 2017: Cell
https://www.readbyqxmd.com/read/29021780/chronic-5-aminoimidazole-4-carboxamide-1-%C3%AE-d-ribofuranoside-treatment-induces-phenotypic-changes-in-skeletal-muscle-but-does-not-improve-disease-outcomes-in-the-r6-2-mouse-model-of-huntington-s-disease
#18
Marie-France Paré, Bernard J Jasmin
Huntington's disease (HD) is an autosomal dominant neurodegenerative genetic disorder characterized by motor, cognitive, and psychiatric symptoms. It is well established that regular physical activity supports brain health, benefiting cognitive function, mental health as well as brain structure and plasticity. Exercise mimetics (EMs) are a group of drugs and small molecules that target signaling pathways in skeletal muscle known to be activated by endurance exercise. The EM 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) has been shown to induce cognitive benefits in healthy mice...
2017: Frontiers in Neurology
https://www.readbyqxmd.com/read/29019003/role-of-dynein-axonemal-heavy-chain-6-gene-expression-as-a-possible-biomarker-for-huntington-s-disease-a-translational-study
#19
Lorena B Areal, Lorraine P Pereira, Fabiola M Ribeiro, Isabella G Olmo, Marcelo R Muniz, Maria do Carmo Rodrigues, Patrik F Costa, Cristina Martins-Silva, Stephen S G Ferguson, Daniela A M Guimarães, Rita G W Pires
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor dysfunction, cognitive deficits, and psychiatric symptoms. The primary genetic cause is an expansion of cytosine adenine guanine (CAG) nucleotides of the huntingtin gene, which codes an important protein involved with neuronal signaling. The severity of HD correlates with the number of CAG repeats and individuals with longer expansions have an earlier onset and more severe symptoms. A microarray study conducted by our research group showed alteration in DNAH6 gene (encoding dynein axonemal heavy chain 6)...
October 10, 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/28993428/disease-modifying-effects-of-ganglioside-gm1-in-huntington-s-disease-models
#20
Melanie Alpaugh, Danny Galleguillos, Juan Forero, Luis Carlos Morales, Sebastian W Lackey, Preeti Kar, Alba Di Pardo, Andrew Holt, Bradley J Kerr, Kathryn G Todd, Glen B Baker, Karim Fouad, Simonetta Sipione
Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive and psychiatric problems. Previous studies indicated that levels of brain gangliosides are lower than normal in HD models and that administration of exogenous ganglioside GM1 corrects motor dysfunction in the YAC128 mouse model of HD In this study, we provide evidence that intraventricular administration of GM1 has profound disease-modifying effects across HD mouse models with different genetic background...
November 2017: EMBO Molecular Medicine
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