Database : MEDLINE
Search on : Huntington and Disease [Words]
References found : 16581 [refine]
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[PMID]: 29510748
[Au] Autor:Ehrnhoefer DE; Martin DDO; Schmidt ME; Qiu X; Ladha S; Caron NS; Skotte NH; Nguyen YTN; Vaid K; Southwell AL; Engemann S; Franciosi S; Hayden MR
[Ad] Address:Centre for Molecular Medicine and Therapeutics (CMMT), CFRI, Department of Medical Genetics, University of British Columbia, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada. ehrnhoefer@bio.mx.
[Ti] Title:Preventing mutant huntingtin proteolysis and intermittent fasting promote autophagy in models of Huntington disease.
[So] Source:Acta Neuropathol Commun;6(1):16, 2018 03 06.
[Is] ISSN:2051-5960
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract: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. These findings may explain the previously observed neuroprotective properties of C6R mHTT. As the C6R mutation cannot be easily translated into a therapeutic approach, we show that a scheduled feeding paradigm is sufficient to lower mHTT levels in YAC128 mice expressing cleavable mHTT. This is consistent with a previous model, where the presence of cleavable mHTT impairs basal autophagy, while fasting-induced autophagy remains functional. In HD, mHTT clearance and autophagy may become increasingly impaired as a function of age and disease stage, because of gradually increased activity of mHTT-processing enzymes. Our findings imply that mHTT clearance could be enhanced by a regulated dietary schedule that promotes autophagy.
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Entry month:1803
[Cu] Class update date: 180311
[Lr] Last revision date:180311
[St] Status:In-Process
[do] DOI:10.1186/s40478-018-0518-0

  2 / 16581 MEDLINE  
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[PMID]: 29499308
[Au] Autor:Monteiro O; Chen C; Bingham R; Argyrou A; Buxton R; Pancevac Jönsson C; Jones E; Bridges A; Gatfield K; Krauß S; Lambert J; Langston R; Schweiger S; Uings I
[Ad] Address:Division of Neuroscience, University of Dundee, UK.
[Ti] Title:Pharmacological disruption of the MID1/α4 interaction reduces mutant Huntingtin levels in primary neuronal cultures.
[So] Source:Neurosci Lett;673:44-50, 2018 Feb 27.
[Is] ISSN:1872-7972
[Cp] Country of publication:Ireland
[La] Language:eng
[Ab] Abstract: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 Hdh mice. This data serves to validate this pathway and paves the way for the discovery of small molecule inhibitors of this interaction as potential therapies for HD.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:Publisher

  3 / 16581 MEDLINE  
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[PMID]: 29435951
[Au] Autor:Pierzynowska K; Gaffke L; Hac A; Mantej J; Niedzialek N; Brokowska J; Wegrzyn G
[Ad] Address:Department of Molecular Biology, University of Gdansk, Wita Stwosza 59, 80-308, Gdansk, Poland.
[Ti] Title:Correction of Huntington's Disease Phenotype by Genistein-Induced Autophagy in the Cellular Model.
[So] Source:Neuromolecular Med;20(1):112-123, 2018 Mar.
[Is] ISSN:1559-1174
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Huntington's disease (HD) is a monogenic disorder, caused by mutations in the HTT gene which result in expansion of CAG triplets. The product of the mutated gene is misfolded huntingtin protein that forms aggregates leading to impairment of neuronal function, neurodegeneration, motor abnormalities and cognitive deficits. No effective cure is currently available for HD. Here we studied effects of genistein (trihydroxyisoflavone) on a HD cellular model consisting of HEK-293 cells transfected with a plasmid bearing mutated HTT gene. Both level of mutated huntingtin and number of aggregates were significantly decreased in genistein-treated HD cell model. This led to increased viability of the cells. Autophagy was up-regulated while inhibition of lysosomal functions by chloroquine impaired the genistein-mediated degradation of the mutated huntingtin aggregates. Hence, we conclude that through stimulating autophagy, genistein removes the major pathogenic factor of HD. Prolonged induction of autophagy was suspected previously to be risky for patients due to putative adverse effects; however, genistein has been demonstrated recently to be safe and suitable for long-term therapies even at doses as high as 150 mg/kg/day. Therefore, results presented in this report provide a basis for the use of genistein in further studies on development of the potential treatment of HD.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180311
[Lr] Last revision date:180311
[St] Status:In-Data-Review
[do] DOI:10.1007/s12017-018-8482-1

  4 / 16581 MEDLINE  
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[PMID]: 29523800
[Au] Autor:Byrne LM; Rodrigues FB; Johnson EB; De Vita E; Blennow K; Scahill R; Zetterberg H; Heslegrave A; Wild EJ
[Ad] Address:Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK.
[Ti] Title:Cerebrospinal fluid neurogranin and TREM2 in Huntington's disease.
[So] Source:Sci Rep;8(1):4260, 2018 Mar 09.
[Is] ISSN:2045-2322
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Biomarkers of Huntington's disease (HD) in cerebrospinal fluid (CSF) could be of value in elucidating the biology of this genetic neurodegenerative disease, as well as in the development of novel therapeutics. Deranged synaptic and immune function have been reported in HD, and concentrations of the synaptic protein neurogranin and the microglial protein TREM2 are increased in other neurodegenerative diseases. We therefore used ELISAs to quantify neurogranin and TREM2 in CSF samples from HD mutation carriers and controls. CSF neurogranin concentration was not significantly altered in HD compared to controls, nor was it significantly associated with disease burden score, total functional capacity or motor score. An apparent increase in CSF TREM2 in manifest HD was determined to be due to increasing TREM2 with age. After age adjustment, there was no significant alteration of TREM2 in either HD group, nor any association with motor, functional or cognitive score, or brain volume quantified by MRI. Both analyses were well-powered, and sample size calculations indicated that several thousand samples per group would be needed to prove that disease-associated alterations do in fact exist. We conclude that neither neurogranin nor TREM2 is a useful biofluid biomarker for disease processes in Huntington's disease.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:In-Data-Review
[do] DOI:10.1038/s41598-018-21788-x

  5 / 16581 MEDLINE  
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[PMID]: 29523769
[Au] Autor:Maiese K
[Ad] Address:Cellular and Molecular Signaling, Newark, NJ 07101, U.S.A. wntin75@yahoo.com.
[Ti] Title:The mechanistic target of rapamycin (mTOR) and the silent mating-type information regulation 2 homolog 1 (SIRT1): oversight for neurodegenerative disorders.
[So] Source:Biochem Soc Trans;, 2018 Mar 09.
[Is] ISSN:1470-8752
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:As a result of the advancing age of the global population and the progressive increase in lifespan, neurodegenerative disorders continue to increase in incidence throughout the world. New strategies for neurodegenerative disorders involve the novel pathways of the mechanistic target of rapamycin (mTOR) and the silent mating-type information regulation 2 homolog 1 ( ) (SIRT1) that can modulate pathways of apoptosis and autophagy. The pathways of mTOR and SIRT1 are closely integrated. mTOR forms the complexes mTOR Complex 1 and mTOR Complex 2 and can impact multiple neurodegenerative disorders that include Alzheimer's disease, Huntington's disease, and Parkinson's disease. SIRT1 can control stem cell proliferation, block neuronal injury through limiting programmed cell death, drive vascular cell survival, and control clinical disorders that include dementia and retinopathy. It is important to recognize that oversight of programmed cell death by mTOR and SIRT1 requires a fine degree of precision to prevent the progression of neurodegenerative disorders. Additional investigations and insights into these pathways should offer effective and safe treatments for neurodegenerative disorders.
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Em] Entry month:1803
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:Publisher

  6 / 16581 MEDLINE  
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[PMID]: 29523177
[Au] Autor:López-Hurtado A; Burgos DF; González P; Dopazo XM; González V; Rábano A; Mellström B; Naranjo JR
[Ad] Address:Spanish Network for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
[Ti] Title:Inhibition of DREAM-ATF6 interaction delays onset of cognition deficit in a mouse model of Huntington's disease.
[So] Source:Mol Brain;11(1):13, 2018 Mar 09.
[Is] ISSN:1756-6606
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:The transcriptional repressor DREAM (downstream regulatory element antagonist modulator) is a multifunctional neuronal calcium sensor (NCS) that controls Ca and protein homeostasis through gene regulation and protein-protein interactions. Downregulation of DREAM is part of an endogenous neuroprotective mechanism that improves ATF6 (activating transcription factor 6) processing, neuronal survival in the striatum, and motor coordination in R6/2 mice, a model of Huntington's disease (HD). Whether modulation of DREAM activity can also ameliorate cognition deficits in HD mice has not been studied. Moreover, it is not known whether DREAM downregulation in HD is unique, or also occurs for other NCS family members. Using the novel object recognition test, we show that chronic administration of the DREAM-binding molecule repaglinide, or induced DREAM haplodeficiency delays onset of cognitive impairment in R6/1 mice, another HD model. The mechanism involves a notable rise in the levels of transcriptionally active ATF6 protein in the hippocampus after repaglinide administration. In addition, we show that reduction in DREAM protein in the hippocampus of HD patients was not accompanied by downregulation of other NCS family members. Our results indicate that DREAM inhibition markedly improves ATF6 processing in the hippocampus and that it might contribute to a delay in memory decline in HD mice. The mechanism of neuroprotection through DREAM silencing in HD does not apply to other NCS family members.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:In-Data-Review
[do] DOI:10.1186/s13041-018-0359-6

  7 / 16581 MEDLINE  
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[PMID]: 29512295
[Au] Autor:Holley SM; Kamdjou T; Reidling JC; Fury B; Coleal-Bergum D; Bauer G; Thompson LM; Levine MS; Cepeda C
[Ad] Address:Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
[Ti] Title:Therapeutic effects of stem cells in rodent models of Huntington's disease: Review and electrophysiological findings.
[So] Source:CNS Neurosci Ther;, 2018 Mar 06.
[Is] ISSN:1755-5949
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:The principal symptoms of Huntington's disease (HD), chorea, cognitive deficits, and psychiatric symptoms are associated with the massive loss of striatal and cortical projection neurons. As current drug therapies only partially alleviate symptoms, finding alternative treatments has become peremptory. Cell replacement using stem cells is a rapidly expanding field that offers such an alternative. In this review, we examine recent studies that use mesenchymal cells, as well as pluripotent, cell-derived products in animal models of HD. Additionally, we provide further electrophysiological characterization of a human neural stem cell line, ESI-017, which has already demonstrated disease-modifying properties in two mouse models of HD. Overall, the field of regenerative medicine represents a viable and promising avenue for the treatment of neurodegenerative disorders including HD.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:Publisher
[do] DOI:10.1111/cns.12839

  8 / 16581 MEDLINE  
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[PMID]: 29484607
[Au] Autor:Niemann N; Jankovic J
[Ad] Address:Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, 7200 Cambridge, Suite 9A, Houston, TX, 77030, USA.
[Ti] Title:Treatment of Tardive Dyskinesia: A General Overview with Focus on the Vesicular Monoamine Transporter 2 Inhibitors.
[So] Source:Drugs;, 2018 Feb 26.
[Is] ISSN:1179-1950
[Cp] Country of publication:New Zealand
[La] Language:eng
[Ab] Abstract:Tardive dyskinesia (TD) encompasses the spectrum of iatrogenic hyperkinetic movement disorders following exposure to dopamine receptor-blocking agents (DRBAs). Despite the advent of atypical or second- and third-generation antipsychotics with a presumably lower risk of complications, TD remains a persistent and challenging problem. Prevention is the first step in mitigating the risk of TD, but early recognition, gradual withdrawal of offending medications, and appropriate treatment are also critical. As TD is often a persistent and troublesome disorder, specific antidyskinetic therapies are often needed for symptomatic relief. The vesicular monoamine transporter 2 (VMAT2) inhibitors, which include tetrabenazine, deutetrabenazine, and valbenazine, are considered the treatment of choice for most patients with TD. Deutetrabenazine-a deuterated version of tetrabenazine-and valbenazine, the purified parent product of one of the main tetrabenazine metabolites, are novel VMAT2 inhibitors and the only drugs to receive approval from the US FDA for the treatment of TD. VMAT2 inhibitors deplete presynaptic dopamine and reduce involuntary movements in many hyperkinetic movement disorders, particularly TD, Huntington disease, and Tourette syndrome. The active metabolites of the VMAT2 inhibitors have high affinity for VMAT2 and minimal off-target binding. Compared with tetrabenazine, deutetrabenazine and valbenazine have pharmacokinetic advantages that translate into less frequent dosing and better tolerability. However, no head-to-head studies have compared the various VMAT2 inhibitors. One of the major advantages of VMAT2 inhibitors over DRBAs, which are still being used by some clinicians in the treatment of some hyperkinetic disorders, including TD, is that they are not associated with the development of TD. We also briefly discuss other treatment options for TD, including amantadine, clonazepam, Gingko biloba, zolpidem, botulinum toxin, and deep brain stimulation. Treatment of TD and other drug-induced movement disorders must be individualized and based on the severity, phenomenology, potential side effects, and other factors discussed in this review.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:Publisher
[do] DOI:10.1007/s40265-018-0874-x

  9 / 16581 MEDLINE  
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[PMID]: 29463644
[Au] Autor:Chan SMH; Lowe MP; Bernard A; Miller AA; Herbert TP
[Ad] Address:School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia.
[Ti] Title:The inositol-requiring enzyme 1 (IRE1α) RNAse inhibitor, 4µ8C, is also a potent cellular antioxidant.
[So] Source:Biochem J;475(5):923-929, 2018 Mar 09.
[Is] ISSN:1470-8728
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Inositol-requiring enzyme 1 alpha (IRE1α) is an endoplasmic reticulum (ER)-transmembrane endonuclease that is activated in response to ER stress as part of the unfolded protein response (UPR). Chronic activation of the UPR has been implicated in the pathogenesis of many common diseases including diabetes, cancer, and neurological pathologies such as Huntington's and Alzheimer's disease. 7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde (4µ8C) is widely used as a specific inhibitor of IRE1α ribonuclease activity (IC of 6.89 µM in cultured cells). However, in this paper, we demonstrate that 4µ8C acts as a potent reactive oxygen species (ROS) scavenger, both in a cell-free assay and in cultured cells, at concentrations lower than that widely used to inhibit IRE1α activity. we show that, 4µ8C effectively decreases xanthine/xanthine oxidase catalysed superoxide production with an IC of 0.2 µM whereas in cultured endothelial and clonal pancreatic ß-cells, 4µ8C inhibits angiotensin II-induced ROS production with IC values of 1.92 and 0.29 µM, respectively. In light of this discovery, conclusions reached using 4µ8C as an inhibitor of IRE1α should be carefully evaluated. However, this unexpected off-target effect of 4µ8C may prove therapeutically advantageous for the treatment of pathologies that are thought to be caused by, or exacerbated by, both oxidative and ER stress such as endothelial dysfunction and/or diabetes.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:In-Data-Review
[do] DOI:10.1042/BCJ20170678

  10 / 16581 MEDLINE  
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[PMID]: 29378223
[Au] Autor:Arab A; Wojna-Pelczar A; Khairnar A; Szabó N; Ruda-Kucerova J
[Ad] Address:Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
[Ti] Title:Principles of diffusion kurtosis imaging and its role in early diagnosis of neurodegenerative disorders.
[So] Source:Brain Res Bull;139:91-98, 2018 Jan 31.
[Is] ISSN:1873-2747
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Pathology of neurodegenerative diseases can be correlated with intra-neuronal as well as extracellular changes which lead to neuronal degeneration. The central nervous system (CNS) is a complex structure comprising of many biological barriers. These microstructural barriers might be affected by a variety of pathological processes. Specifically, changes in the brain tissue's microstructure affect the diffusion of water which can be assessed non-invasively by diffusion weighted (DW) magnetic resonance imaging (MRI) techniques. Diffusion tensor imaging (DTI) is a diffusion MRI technique that considers diffusivity as a Gaussian process, i.e. does not account for any diffusion hindrance. However, environment of the brain tissues is characterized by a non-Gaussian diffusion. Therefore, diffusion kurtosis imaging (DKI) was developed as an extension of DTI method in order to quantify the non-Gaussian distribution of water diffusion. This technique represents a promising approach for early diagnosis of neurodegenerative diseases when the neurodegenerative process starts. Hence, the purpose of this article is to summarize the ongoing clinical and preclinical research on Parkinson's, Alzheimer's and Huntington diseases, using DKI and to discuss the role of this technique as an early stage biomarker of neurodegenerative conditions.
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Em] Entry month:1801
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[St] Status:Publisher


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