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https://www.readbyqxmd.com/read/28642124/identification-of-genetic-variants-associated-with-huntington-s-disease-progression-a-genome-wide-association-study
#1
Davina J Hensman Moss, Antonio F Pardiñas, Douglas Langbehn, Kitty Lo, Blair R Leavitt, Raymund Roos, Alexandra Durr, Simon Mead, Peter Holmans, Lesley Jones, Sarah J Tabrizi
BACKGROUND: Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. METHODS: We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008-11)...
June 19, 2017: Lancet Neurology
https://www.readbyqxmd.com/read/28639241/huntington-s-disease-and-mitochondria
#2
REVIEW
Mohammad Jodeiri Farshbaf, Kamran Ghaedi
Huntington's disease (HD) as an inherited neurodegenerative disorder leads to neuronal loss in striatum. Progressive motor dysfunction, cognitive decline, and psychiatric disturbance are the main clinical symptoms of the HD. This disease is caused by expansion of the CAG repeats in exon 1 of the huntingtin which encodes Huntingtin protein (Htt). Various cellular and molecular events play role in the pathology of HD. Mitochondria as important organelles play crucial roles in the most of neurodegenerative disorders like HD...
June 21, 2017: Neurotoxicity Research
https://www.readbyqxmd.com/read/28638078/the-stress-response-factor-daf-16-foxo-is-required-for-multiple-compound-families-to-prolong-the-function-of-neurons-with-huntington-s-disease
#3
Francesca Farina, Emmanuel Lambert, Lucie Commeau, François-Xavier Lejeune, Nathalie Roudier, Cosima Fonte, J Alex Parker, Jacques Boddaert, Marc Verny, Etienne-Emile Baulieu, Christian Neri
Helping neurons to compensate for proteotoxic stress and maintain function over time (neuronal compensation) has therapeutic potential in aging and neurodegenerative disease. The stress response factor FOXO3 is neuroprotective in models of Huntington's disease (HD), Parkinson's disease and motor-neuron diseases. Neuroprotective compounds acting in a FOXO-dependent manner could thus constitute bona fide drugs for promoting neuronal compensation. However, whether FOXO-dependent neuroprotection is a common feature of several compound families remains unknown...
June 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28633139/mitochondrial-metabolism-in-a-large-animal-model-of-huntington-disease-the-hunt-for-biomarkers-in-the-spermatozoa-of-presymptomatic-minipigs
#4
Jana Krizova, Hana Stufkova, Marie Rodinova, Monika Macakova, Bozena Bohuslavova, Daniela Vidinska, Jiri Klima, Zdenka Ellederova, Antonin Pavlok, David S Howland, Jiri Zeman, Jan Motlik, Hana Hansikova
BACKGROUND: Huntington disease (HD) is a fatal neurodegenerative disorder involving reduced muscle coordination, mental and behavioral changes, and testicular degeneration. In order to further clarify the decreased fertility and penetration ability of the spermatozoa of transgenic HD minipig boars (TgHD), we applied a set of mitochondrial metabolism (MM) parameter measurements to this promising biological material, which can be collected noninvasively in longitudinal studies. OBJECTIVE: We aimed to optimize methods for MM measurements in spermatozoa and to establish possible biomarkers of HD in TgHD spermatozoa expressing the N-terminal part of mutated human huntingtin...
June 21, 2017: Neuro-degenerative Diseases
https://www.readbyqxmd.com/read/28632780/metformin-intake-associates-with-better-cognitive-function-in-patients-with-huntington-s-disease
#5
David Hervás, Victoria Fornés-Ferrer, Ana Pilar Gómez-Escribano, María Dolores Sequedo, Carmen Peiró, José María Millán, Rafael P Vázquez-Manrique
Huntington's disease (HD) is an inherited, dominant neurodegenerative disorder caused by an abnormal expansion of CAG triplets in the huntingtin gene (htt). Despite extensive efforts to modify the progression of HD thus far only symptomatic treatment is available. Recent work suggests that treating invertebrate and mice HD models with metformin, a well-known AMPK activator which is used worldwide to treat type 2-diabetes, reduces mutant huntingtin from cells and alleviates many of the phenotypes associated to HD...
2017: PloS One
https://www.readbyqxmd.com/read/28632387/poly-trehalose-nanoparticle-prevents-amyloid-aggregation-and-suppress-polyglutamine-aggregation-in-huntington-s-disease-model-mouse
#6
Koushik Debnath, Nibedita Pradhan, Brijesh Kumar Singh, Nihar R Jana, Nikhil R Jana
Prevention and therapeutic strategy of various neurodegenerative disease focus on inhibiting protein fibrillation, clearing of aggregated protein plaques from brain and lowering of protein aggregate-induced toxicity. We have designed poly(trehalose) nanoparticle that can inhibit amyloid/polyglutamine aggregation under extra-/intra-cellular condition, reduce such aggregation-derived cytotoxicity and prevents polyglutamine aggregation in Huntington's disease (HD) model mouse brain. Nanoparticle has 20-30 nm hydrodynamic size, composed of 6 nm iron oxide core and zwitterionic polymer shell with covalently linked trehalose of ~5-12 wt %...
June 20, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28628038/crispr-cas9-mediated-gene-editing-ameliorates-neurotoxicity-in-mouse-model-of-huntington-s-disease
#7
Su Yang, Renbao Chang, Huiming Yang, Ting Zhao, Yan Hong, Ha Eun Kong, Xiaobo Sun, Zhaohui Qin, Peng Jin, Shihua Li, Xiao-Jiang Li
Huntington's disease is a neurodegenerative disorder caused by a polyglutamine repeat in the Huntingtin gene (HTT). Although suppressing the expression of mutant HTT (mHTT) has been explored as a therapeutic strategy to treat Huntington's disease, considerable efforts have gone into developing allele-specific suppression of mHTT expression, given that loss of Htt in mice can lead to embryonic lethality. It remains unknown whether depletion of HTT in the adult brain, regardless of its allele, could be a safe therapy...
June 19, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28624208/safe-and-efficient-silencing-with-a-pol-ii-but-not-a-pol-lii-promoter-expressing-an-artificial-mirna-targeting-human-huntingtin
#8
Edith L Pfister, Kathryn O Chase, Huaming Sun, Lori A Kennington, Faith Conroy, Emily Johnson, Rachael Miller, Florie Borel, Neil Aronin, Christian Mueller
Huntington's disease is a devastating, incurable neurodegenerative disease affecting up to 12 per 100,000 patients worldwide. The disease is caused by a mutation in the Huntingtin (Htt) gene. There is interest in reducing mutant Huntingtin by targeting it at the mRNA level, but the maximum tolerable dose and long-term effects of such a treatment are unknown. Using a self-complementary AAV9 vector, we delivered a mir-155-based artificial miRNA under the control of the chicken β-actin or human U6 promoter. In mouse brain, the artificial miRNA reduced the human huntingtin mRNA by 50%...
June 16, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28624195/fluorinated-nucleotide-modifications-modulate-allele-selectivity-of-snp-targeting-antisense-oligonucleotides
#9
Michael E Østergaard, Josh Nichols, Timothy A Dwight, Walt Lima, Michael E Jung, Eric E Swayze, Punit P Seth
Antisense oligonucleotides (ASOs) have the potential to discriminate between subtle RNA mismatches such as SNPs. Certain mismatches, however, allow ASOs to bind at physiological conditions and result in RNA cleavage mediated by RNase H. We showed that replacing DNA nucleotides in the gap region of an ASO with other chemical modification can improve allele selectivity. Herein, we systematically substitute every position in the gap region of an ASO targeting huntingtin gene (HTT) with fluorinated nucleotides...
June 16, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28621522/formation-and-structure-of-wild-type-huntingtin-exon-1-fibrils
#10
J Mario Isas, Andreas Langen, Myles C Isas, Nitin Kumar Pandey, Ansgar B Siemer
The fact that the heritable neurodegenerative disorder Huntington's Disease (HD) is autosomal dominant means that there is one wild type and one mutant allele in most HD patients. The CAG repeat expansion in the exon 1 of the protein huntingtin (HTTex1) that causes the disease, leads to the formation of HTT fibrils in vitro and vivo. An important question for understanding the molecular mechanism of HD is which role wild type HTT plays for the formation, propagation, and structure of these HTT fibrils. Here we report that fibrils of mutant HTTex1 are able to seed the aggregation of wild type HTTex1 into amyloid fibrils which in turn can seed the fibril formation of mutant HTTex1...
June 16, 2017: Biochemistry
https://www.readbyqxmd.com/read/28611571/exosomes-and-homeostatic-synaptic-plasticity-are-linked-to-each-other-and-to-huntington-s-parkinson-s-and-other-neurodegenerative-diseases-by-database-enabled-analyses-of-comprehensively-curated-datasets
#11
James K T Wang, Peter Langfelder, Steve Horvath, Michael J Palazzolo
Huntington's disease (HD) is a progressive and autosomal dominant neurodegeneration caused by CAG expansion in the huntingtin gene (HTT), but the pathophysiological mechanism of mutant HTT (mHTT) remains unclear. To study HD using systems biological methodologies on all published data, we undertook the first comprehensive curation of two key PubMed HD datasets: perturbation genes that impact mHTT-driven endpoints and therefore are putatively linked causally to pathogenic mechanisms, and the protein interactome of HTT that reflects its biology...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28609090/emerging-%C3%AE-sheet-rich-conformations-in-super-compact-huntingtin-exon-1-mutant-structures
#12
Hongsuk Kang, Francisco X Vázquez, Leili Zhang, Payel Das, Leticia Marisel Toledo-Sherman, Binquan Luan, Michael Levitt, Ruhong Zhou
There exits strong correlation between the extended poly-glutamines (polyQ) within exon-1 of Huntingtin protein (Htt) and age onset of Huntington's disease (HD), however, the underlying molecular mechanism is still poorly understood. Here we apply extensive molecular dynamics simulations to study the folding of Htt-exon-1 across five different polyQ-lengths. We find an increase in secondary structure motifs at longer Q-lengths, including β-sheet content that seems to contribute to the formation of increasingly compact structures...
June 13, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28606048/immunomodulatory-strategies-for-huntington-s-disease-treatment
#13
Gabriela Delevati Colpo, Natalia Pessoa Rocha, Erin Fur Stimming, Antonio Lucio Teixeira
Huntington's disease (HD) is an autosomal-dominant, progressive neurodegenerative disease characterized by selective loss of neurons in the striatum and cortex, which leads to progressive motor dysfunction, cognitive decline and behavioral symptoms. HD is caused by a trinucleotide (CAG) repeat expansion in the gene encoding for huntingtin (HTT). Despite the fact that the HD gene was identified over 20 years ago, there is no effective disease-modifying therapy for HD and only symptomatic therapies are available to date...
June 12, 2017: CNS & Neurological Disorders Drug Targets
https://www.readbyqxmd.com/read/28603746/preclinical-evaluation-of-a-lentiviral-vector-for-huntingtin-silencing
#14
Karine Cambon, Virginie Zimmer, Sylvain Martineau, Marie-Claude Gaillard, Margot Jarrige, Aurore Bugi, Jana Miniarikova, Maria Rey, Raymonde Hassig, Noelle Dufour, Gwenaelle Auregan, Philippe Hantraye, Anselme L Perrier, Nicole Déglon
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder resulting from a polyglutamine expansion in the huntingtin (HTT) protein. There is currently no cure for this disease, but recent studies suggest that RNAi to downregulate the expression of both normal and mutant HTT is a promising therapeutic approach. We previously developed a small hairpin RNA (shRNA), vectorized in an HIV-1-derived lentiviral vector (LV), that reduced pathology in an HD rodent model. Here, we modified this vector for preclinical development by using a tat-independent third-generation LV (pCCL) backbone and removing the original reporter genes...
June 16, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28596754/angiotensins-and-huntington-s-disease-a-study-on-immortalized-progenitor-striatal-cell-lines
#15
Walmor C De Mello, Yamil Gerena, Sylvette Ayala-Peña
Neurons from mouse models of Huntington's disease (HD) exhibit altered electrophysiological properties, potentially contributing to neuronal dysfunction and neurodegeneration. The renin-angiotensin system (RAS) is a potential contributor to the pathophysiology of neurodegenerative diseases. However, the role of angiotensin II (Ang II) and angiotensin (1-7) has not been characterized in HD. We investigated the influence of Ang II and angiotensin (1-7) on total potassium current using immortalized progenitor mutant huntingtin-expressing (Q111) and wild-type (Q7) cell lines...
2017: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/28593442/remodeling-of-heterochromatin-structure-slows-neuropathological-progression-and-prolongs-survival-in-an-animal-model-of-huntington-s-disease
#16
Junghee Lee, Yu Jin Hwang, Yunha Kim, Min Young Lee, Seung Jae Hyeon, Soojin Lee, Dong Hyun Kim, Sung Jae Jang, Hyoenjoo Im, Sun-Joon Min, Hyunah Choo, Ae Nim Pae, Dong Jin Kim, Kyung Sang Cho, Neil W Kowall, Hoon Ryu
Huntington's disease (HD) is an autosomal-dominant inherited neurological disorder caused by expanded CAG repeats in exon 1 of the Huntingtin (HTT) gene. Altered histone modifications and epigenetic mechanisms are closely associated with HD suggesting that transcriptional repression may play a pathogenic role. Epigenetic compounds have significant therapeutic effects in cellular and animal models of HD, but they have not been successful in clinical trials. Herein, we report that dSETDB1/ESET, a histone methyltransferase (HMT), is a mediator of mutant HTT-induced degeneration in a fly HD model...
June 7, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28590448/striatal-vulnerability-in-huntington-s-disease-neuroprotection-versus-neurotoxicity
#17
REVIEW
Ryoma Morigaki, Satoshi Goto
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by the expansion of a CAG trinucleotide repeat encoding an abnormally long polyglutamine tract (PolyQ) in the huntingtin (Htt) protein. In HD, striking neuropathological changes occur in the striatum, including loss of medium spiny neurons and parvalbumin-expressing interneurons accompanied by neurodegeneration of the striosome and matrix compartments, leading to progressive impairment of reasoning, walking and speaking abilities...
June 7, 2017: Brain Sciences
https://www.readbyqxmd.com/read/28587900/altered-reactivity-of-central-amygdala-to-gabaar-antagonist-in-the-bachd-rat-model-of-huntington-disease
#18
Charlotte Lamirault, Libo Yu-Taeger, Valérie Doyère, Olaf Riess, Huu Phuc Nguyen, Nicole El Massioui
In Huntington's disease (HD), dysfunctional affective processes emerge as key symptoms of disturbances. In human HD and transgenic rat models of the disease, the amygdala was previously shown to have a reduced volume and to carry a high load of mutant huntingtin (mHTT) aggregates. In search of the pathophysiology of affective dysregulation in HD, we hypothesized a specific role of the central amygdala (CeA), known to be particularly involved in emotional regulation. Using transgenic BACHD rats carrying full-length human mHTT, we compared behavioral consequences of pharmacological modulation of CeA function by infusing GABAA receptor (GABAAR) antagonist picrotoxin into ∼4...
June 3, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28585930/large-normal-range-tbp-and-atxn7-cag-repeat-lengths-are-associated-with-increased-lifetime-risk-of-depression
#19
S L Gardiner, M J van Belzen, M W Boogaard, W M C van Roon-Mom, M P Rozing, A M van Hemert, J H Smit, A T F Beekman, G van Grootheest, R A Schoevers, R C Oude Voshaar, H C Comijs, B W J H Penninx, R C van der Mast, R A C Roos, N A Aziz
Depression is one of the most prevalent and debilitating psychiatric disorders worldwide. Recently, we showed that both relatively short and relatively long cytosine-adenine-guanine (CAG) repeats in the huntingtin gene (HTT) are associated with an increased risk of lifetime depression. However, to what extent the variations in CAG repeat length in the other eight polyglutamine disease-associated genes (PDAGs) are associated with depression is still unknown. We determined the CAG repeat sizes of ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, ATN1 and AR 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 individuals-aged 18-93 years...
June 6, 2017: Translational Psychiatry
https://www.readbyqxmd.com/read/28585574/structural-basis-of-hypk-regulating-n-terminal-acetylation-by-the-nata-complex
#20
Felix Alexander Weyer, Andrea Gumiero, Karine Lapouge, Gert Bange, Jürgen Kopp, Irmgard Sinning
In eukaryotes, N-terminal acetylation is one of the most common protein modifications involved in a wide range of biological processes. Most N-acetyltransferase complexes (NATs) act co-translationally, with the heterodimeric NatA complex modifying the majority of substrate proteins. Here we show that the Huntingtin yeast two-hybrid protein K (HypK) binds tightly to the NatA complex comprising the auxiliary subunit Naa15 and the catalytic subunit Naa10. The crystal structures of NatA bound to HypK or to a N-terminal deletion variant of HypK were determined without or with a bi-substrate analogue, respectively...
June 6, 2017: Nature Communications
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