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Mahalakshmi Shankaran, Eleonora Di Paolo, Valerio Leoni, Claudio Caccia, Costanza Ferrari Bardile, Hussein Mohammed, Stefano Di Donato, Seung Kwak, Deanna Marchionini, Scott Turner, Elena Cattaneo, Marta Valenza
Cholesterol precursors and cholesterol levels are reduced in brain regions of Huntington's disease (HD) mice. Here we quantified the rate of in vivo de novo cholesterol biosynthesis in the HD brain. Samples from different brain regions and blood of the heterozygous knock-in mouse model carrying 175 CAG repeats (Q175) at different phenotypic stages were processed independently by two research units to quantify cholesterol synthesis rate by (2)H2O labeling and measure the concentrations of lathosterol, cholesterol and its brain-specific cholesterol catabolite 24-hydroxy-cholesterol (24OHC) by isotope dilution mass spectrometry...
November 29, 2016: Neurobiology of Disease
Daniel R Miranda, Monica Wong, Shannon H Romer, Cynthia McKee, Gabriela Garza-Vasquez, Alyssa C Medina, Volker Bahn, Andrew D Steele, Robert J Talmadge, Andrew A Voss
Huntington's disease (HD) patients suffer from progressive and debilitating motor dysfunction. Previously, we discovered reduced skeletal muscle chloride channel (ClC-1) currents, inwardly rectifying potassium (Kir) channel currents, and membrane capacitance in R6/2 transgenic HD mice. The ClC-1 loss-of-function correlated with increased aberrant mRNA processing and decreased levels of full-length ClC-1 mRNA (Clcn1 gene). Physiologically, the resulting muscle hyperexcitability may help explain involuntary contractions of HD...
November 29, 2016: Journal of General Physiology
Koliane Ouk, Juliet Aungier, A Jennifer Morton
Huntington's disease (HD) is a progressive genetic neurodegenerative disorder characterised by motor and cognitive deficits, as well as sleep and circadian abnormalities. In the R6/2 mouse, a fragment model of HD, rest-activity rhythms controlled by the suprachiasmatic nucleus disintegrate completely by 4months of age. Rhythms driven by a second circadian oscillator, the methamphetamine-sensitive circadian oscillator (MASCO), are disrupted even earlier, and cannot be induced after 2months of age. Here, we studied the effect of the HD mutation on the expression of MASCO-driven rhythms in a more slowly developing, genetically relevant mouse model of HD, the Q175 'knock-in' mouse...
September 16, 2016: Experimental Neurology
Andrew C McCourt, Lovisa Jakobsson, Sara Larsson, Cecilia Holm, Sarah Piel, Eskil Elmér, Maria Björkqvist
Huntington's disease (HD) is a fatal, autosomal dominantly inherited neurodegenerative disorder, characterised not only by progressive cognitive, motor and psychiatric impairments, but also of peripheral pathology. In both human HD and in mouse models of HD there is evidence of increased energy expenditure and weight loss, alongside altered body composition. Unlike white adipose tissue (WAT), brown adipose tissue (BAT), as well as brown-like cells within WAT, expresses the mitochondrial protein, uncoupling protein 1 (UCP1)...
2016: PloS One
Michal Geva, Rebecca Kusko, Holly Soares, Kevin D Fowler, Tal Birnberg, Steve Barash, Avia Merenlender -Wagner, Tania Fine, Andrew Lysaght, Brian Weiner, Yoonjeong Cha, Sarah Kolitz, Fadi Towfic, Aric Orbach, Ralph Laufer, Ben Zeskind, Iris Grossman, Michael R Hayden
Pridopidine has demonstrated improvement in Huntington Disease (HD) motor symptoms as measured by secondary endpoints in clinical trials. Originally described as a dopamine stabilizer, this mechanism is insufficient to explain the clinical and preclinical effects of pridopidine. This study therefore explored pridopidine's potential mechanisms of action. The effect of pridopidine versus sham treatment on genome-wide expression profiling in the rat striatum was analysed and compared to the pathological expression profile in Q175 knock-in (Q175 KI) vs Q25 WT mouse models...
July 27, 2016: Human Molecular Genetics
Amber L Southwell, Amy Smith-Dijak, Chris Kay, Marja Sepers, Erika B Villanueva, Matthew P Parsons, Yuanyun Xie, Lisa Anderson, Boguslaw Felczak, Sabine Waltl, Seunghyun Ko, Daphne Cheung, Louisa Dal Cengio, Ramy Slama, Eugenia Petoukhov, Lynn A Raymond, Michael R Hayden
Huntington disease (HD) model mice with heterozygous knock-in (KI) of an expanded CAG tract in exon 1 of the mouse huntingtin (Htt) gene homolog genetically recapitulate the mutation that causes HD, and might be favored for preclinical studies. However, historically these mice have failed to phenotypically recapitulate the human disease. Thus, homozygous KI mice, which lack wildtype Htt, and are much less relevant to human HD, have been used. The zQ175 model was the first KI mouse to exhibit significant HD-like phenotypes when heterozygous...
July 4, 2016: Human Molecular Genetics
Tenghui Chen, Zixing Wang, Wanding Zhou, Zechen Chong, Funda Meric-Bernstam, Gordon B Mills, Ken Chen
BACKGROUND: An important step towards personalizing cancer treatment is to integrate heterogeneous evidences to catalog mutational hotspots that are biologically and therapeutically relevant and thus represent where targeted therapy would likely be beneficial. However, existing methods do not sufficiently delineate varying functionality of individual mutations within the same genes. RESULTS: We observed a large discordancy of mutation rates across different mutation subtypes and tumor types, and nominated 702 hotspot mutations in 549 genes in the Catalog of Somatic Mutations in Cancer (COSMIC) by considering context specific mutation characteristics such as genes, cancer types, mutation rates, mutation subtypes and sequence contexts...
2016: BMC Genomics
Dan P Covey, Hannah M Dantrassy, Natalie E Zlebnik, Iness Gildish, Joseph F Cheer
UNLABELLED: Huntington's disease (HD) is a heritable neurodegenerative disorder caused by expansion of CAG (glutamine) repeats in the HTT gene. A prodromal stage characterized by psychiatric disturbances normally precedes primary motor symptoms and suppressed motivation represents one of the earliest and most common psychiatric symptoms. Although dopamine in the nucleus accumbens (NAc) critically regulates motivation and altered dopamine signaling is implicated in HD, the nature of dopaminergic deficits and contribution to symptoms in HD is poorly understood...
May 4, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Anton Dvorzhak, Tatyana Vagner, Knut Kirmse, Rosemarie Grantyn
UNLABELLED: This study evaluates single-cell indicators of glutamate transport in sulforhodamine 101-positive astrocytes of Q175 mice, a knock-in model of Huntington's disease (HD). Transport-related fluorescent ratio signals obtained with sodium-binding benzofuran isophtalate (SBFI) AM from unperturbed or voltage-clamped astrocytes and respective glutamate transporter currents (GTCs) were induced by photolytic or synaptic glutamate release and isolated pharmacologically. The HD-induced deficit ranged from -27% (GTC maximum at -100 mV in Ba(2+)) to -41% (sodium transients in astrocytes after loading SBFI-AM)...
May 4, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
A B Wehner, A M Milen, R L Albin, B A Pierchala
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder characterized by a constellation of motor, cognitive, and psychiatric features. Striatal medium spiny neurons, one of the most affected populations, are dependent on brain-derived neurotrophic factor (BDNF) anterogradely transported from the cortex for proper function and survival. Recent studies suggest both receptors for BDNF, TrkB and p75 neurotrophin receptor (p75), are improperly regulated in the striata of HD patients and mouse models of HD...
June 2, 2016: Neuroscience
T Rothe, M Deliano, A M Wójtowicz, A Dvorzhak, D Harnack, S Paul, T Vagner, I Melnick, H Stark, R Grantyn
Huntington's disease (HD) is a severe genetically inherited neurodegenerative disorder. Patients present with three principal phenotypes of motor symptoms: choreatic, hypokinetic-rigid and mixed. The Q175 mouse model of disease offers an opportunity to investigate the cellular basis of the hypokinetic-rigid form of HD. At the age of 1 year homozygote Q175 mice exhibited the following signs of hypokinesia: Reduced frequency of spontaneous movements on a precision balance at daytime (-55%), increased total time spent without movement in an open field (+42%), failures in the execution of unconditioned avoidance reactions (+32%), reduced ability for conditioned avoidance (-96%) and increased reaction times (+65%) in a shuttle box...
December 17, 2015: Neuroscience
Nima N Naseri, Hui Xu, Joseph Bonica, Jean Paul G Vonsattel, Etty P Cortes, Larry C Park, Jamshid Arjomand, Gary E Gibson
Glucose metabolism is reduced in the brains of patients with Huntington disease (HD). The mechanisms underlying this deficit, its link to the pathology of the disease, and the vulnerability of the striatum in HD remain unknown. Abnormalities in some of the key mitochondrial enzymes involved in glucose metabolism, including the pyruvate dehydrogenase complex (PDHC) and the tricarboxylic acid (TCA) cycle, may contribute to these deficits. Here, activities for these enzymes and select protein levels were measured in human postmortem cortex and in striatum and cortex of an HD mouse model (Q175); mRNA levels encoding for these enzymes were also measured in the Q175 mouse cortex...
June 2015: Journal of Neuropathology and Experimental Neurology
Tim Indersmitten, Conny H Tran, Carlos Cepeda, Michael S Levine
The Q175 knockin mouse model of Huntington's disease (HD) carries a CAG trinucleotide expansion of the human mutant huntingtin allele in its native mouse genomic context and recapitulates the genotype more closely than transgenic models. In this study we examined the progression of changes in intrinsic membrane properties and excitatory and inhibitory synaptic transmission, using whole cell patch-clamp recordings of medium-sized spiny neurons (MSNs) in the dorsolateral striatum and cortical pyramidal neurons (CPNs) in layers 2/3 of the primary motor cortex in brain slices from heterozygous (Q175(+/-)) and homozygous (Q175(+/+)) mice...
April 1, 2015: Journal of Neurophysiology
Dávid Nagy, Francis D Tingley, Milan Stoiljkovic, Mihály Hajós
Several neurophysiological abnormalities have been described in Huntington's disease, including auditory gating deficit, which are considered to reflect impaired brain information-processing. Since transgenic animal models of Huntington's disease capture basic neuropathology of the disorder, auditory gating was studied in BACHD (line5) transgenic rats and Q175 transgenic mice, together with local field gamma power in the hippocampus and primary auditory cortex. Using clinically equivalent acoustic-stimulation paradigms, impaired auditory gating was detected in transgenic BACHD rats under anesthesia and in freely-moving condition...
January 2015: Experimental Neurology
Maud Gratuze, Anastasia Noël, Carl Julien, Giulia Cisbani, Philippe Milot-Rousseau, Françoise Morin, Maya Dickler, Claudia Goupil, François Bezeau, Isabelle Poitras, Stéphanie Bissonnette, Robert A Whittington, Sébastien S Hébert, Francesca Cicchetti, J Alex Parker, Pershia Samadi, Emmanuel Planel
Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by polyglutamine expansions in the amino-terminal region of the huntingtin (Htt) protein. At the cellular level, neuronal death is accompanied by the proteolytic cleavage, misfolding and aggregation of huntingtin. Abnormal hyperphosphorylation of tau protein is a characteristic feature of a class of neurodegenerative diseases called tauopathies. As a number of studies have reported tau pathology in HD patients, we investigated whether HD pathology may promote tau hyperphosphorylation and if so tackle some of its underlying mechanisms...
January 1, 2015: Human Molecular Genetics
Craig F Ferris, Praveen Kulkarni, Steven Toddes, Jason Yee, William Kenkel, Mark Nedelman
Blood oxygen level dependent (BOLD) imaging in awake mice was used to identify differences in brain activity between wild-type, HETzQ175, and HOMzQ175 genotypes in response to the odor of almond. The study was designed to see how alterations in the huntingtin gene in a mouse model of Huntington's disease would affect the perception and processing of almond odor, an evolutionarily conserved stimulus with high emotional and motivational valence. Moreover, the mice in this study were "odor naïve," i.e., never having smelled almond or any nuts...
2014: Frontiers in Neurology
Petr Vodicka, Junghyun Lim, Dana T Williams, Kimberly B Kegel, Kathryn Chase, Hyunsun Park, Deanna Marchionini, Stephen Wilkinson, Tania Mead, Helen Birch, Dawn Yates, Kathy Lyons, Celia Dominguez, Maria Beconi, Zhenyu Yue, Neil Aronin, Marian DiFiglia
BACKGROUND: Increasing mutant huntingtin (mHTT) clearance through the autophagy pathway may be a way to treat Huntington's disease (HD). Tools to manipulate and measure autophagy flux in brain in vivo are not well established. OBJECTIVE: To examine the in vivo pharmacokinetics and pharmacodynamics of the lysosomal inhibitor chloroquine (CQ) and the levels of selected autophagy markers to determine usefulness of CQ as a tool to study autophagy flux in brain. METHODS: Intraperitoneal injections of CQ were administered to WT and HD(Q175/Q175) mice...
2014: Journal of Huntington's Disease
Anna Magnusson-Lind, Marcus Davidsson, Edina Silajdžić, Christian Hansen, Andrew C McCourt, Sarah J Tabrizi, Maria Björkqvist
BACKGROUND: In addition to classical neurological symptoms, Huntington's disease (HD) is complicated by peripheral pathology, including progressive skeletal muscle wasting, and common skeletal muscle gene expression changes have been shown in HD mice and human HD. OBJECTIVE: To highlight possible mechanisms underlying muscle wasting in HD, we examined gene expression in pathways governing skeletal muscle contractility, skeletal myogenesis, skeletal muscle wasting, apoptosis and the NFκB signaling pathway in two HD mouse models (the transgenic R6/2 and full-length knock-in Q175)...
2014: Journal of Huntington's Disease
Gaynor A Smith, Emily M Rocha, Jesse R McLean, Melissa A Hayes, Sarah C Izen, Ole Isacson, Penelope J Hallett
A long-term goal of modeling Huntington's disease (HD) is to recapitulate the cardinal features of the disease in mice that express both mutant and wild-type (WT) huntingtin (Htt), as HD commonly manifests as a heterozygous condition in humans, and loss of WT Htt is associated with loss-of-function. In a new heterozygous Q175 knock-in (KI) mouse model, we performed an extensive evaluation of motor and cognitive functional deficits, neuropathological and biochemical changes and levels of proteins involved in synaptic function, the cytoskeleton and axonal transport, at 1-16 months of age...
September 1, 2014: Human Molecular Genetics
Xiaoping Tong, Yan Ao, Guido C Faas, Sinifunanya E Nwaobi, Ji Xu, Martin D Haustein, Mark A Anderson, Istvan Mody, Michelle L Olsen, Michael V Sofroniew, Baljit S Khakh
Huntington's disease (HD) is characterized by striatal medium spiny neuron (MSN) dysfunction, but the underlying mechanisms remain unclear. We explored roles for astrocytes, in which mutant huntingtin is expressed in HD patients and mouse models. We found that symptom onset in R6/2 and Q175 HD mouse models was not associated with classical astrogliosis, but was associated with decreased Kir4.1 K(+) channel functional expression, leading to elevated in vivo striatal extracellular K(+), which increased MSN excitability in vitro...
May 2014: Nature Neuroscience
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