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YAC128 mouse

Marta Garcia-Miralles, Nur Amirah Binte Mohammad Yusof, Jing Ying Tan, Carola I Radulescu, Harwin Sidik, Liang Juin Tan, Haim Belinson, Neta Zach, Michael R Hayden, Mahmoud A Pouladi
Laquinimod, an immunomodulatory agent under clinical development for Huntington disease (HD), has recently been shown to confer behavioural improvements that are coupled with prevention of atrophy of the white matter (WM)-rich corpus callosum (CC) in the YAC128 HD mice. However, the nature of the WM improvements is not known yet. Here we investigated the effects of laquinimod on HD-related myelination deficits at the cellular, molecular and ultrastructural levels. We showed that laquinimod treatment improves motor learning and motor function deficits in YAC128 HD mice, and confirmed its antidepressant effect even at the lowest dose used...
October 17, 2018: Molecular Neurobiology
Ellen Teresa Koch, Cameron L Woodard, Lynn Alison Raymond
Glutamate is the main excitatory neurotransmitter in the brain, and impairments in its signaling are associated with many neurological disorders, including Huntington's Disease (HD). Previous studies in HD mouse models demonstrate altered glutamate receptor distribution and signaling at cortico-striatal synapses, and some studies suggest glutamate release is altered; however, traditional methods to study synaptic glutamate release are indirect or have poor temporal resolution. Here we utilize iGluSnFR, a modified GFP reporter for real-time imaging of glutamate transmission, to study presynaptic modulation of cortical glutamate release in the striatum of the YAC128 HD mouse model...
October 17, 2018: Journal of Neurophysiology
Wei-Tang Chang, Fiftarina Puspitasari, Marta Garcia-Miralles, Ling Yun Yeow, Hui-Chien Tay, Katrianne Bethia Koh, Liang Juin Tan, Mahmoud A Pouladi, Kai-Hsiang Chuang
Recent studies suggest that neurodegenerative diseases could affect brain structure and function in disease-specific network patterns; however, how spontaneous activity affects structural covariance network (SC) is not clear. We hypothesized that hyper-excitability in Huntington disease (HD) disrupts the coordinated structural and functional connectivity, and treatment with memantine helps to reduce excitotoxicity and normalize the connectivity. MRI was conducted to measure somatosensory activation, resting-state functional-connectivity (rsFC), SC, amplitude of low frequency fluctuation (ALFF) and ALFF covariance (ALFFC) in the YAC128 mouse model of HD...
September 27, 2018: NMR in Biomedicine
Cristine de Paula Nascimento-Castro, Ana Claudia Wink, Victor Silva da Fônseca, Claudia Daniele Bianco, Elisa C Winkelmann-Duarte, Marcelo Farina, Ana Lúcia S Rodrigues, Joana Gil-Mohapel, Andreza Fabro de Bem, Patricia S Brocardo
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a trinucleotide expansion in the HD gene, resulting in an extended polyglutamine tract in the protein huntingtin. HD is traditionally viewed as a movement disorder, but cognitive and neuropsychiatric symptoms also contribute to the clinical presentation. Depression is one of the most common psychiatric disturbances in HD, present even before manifestation of motor symptoms. Diagnosis and treatment of depression in HD-affected individuals are essential aspects of clinical management in this population, especially owing to the high risk of suicide...
2018: Neural Plasticity
Mandi E Schmidt, Caodu Buren, James P Mackay, Daphne Cheung, Louisa Dal Cengio, Lynn A Raymond, Michael R Hayden
BACKGROUND: Huntington disease (HD) is a fatal neurodegenerative disorder caused by a CAG expansion in the huntingtin (HTT) gene, leading to selective and progressive neuronal death predominantly in the striatum. Mutant HTT expression causes dysfunctional cortico-striatal (CS) transmission, loss of CS synapses, and striatal medium spiny neuron (MSN) dendritic spine instability prior to neuronal death. Co-culturing cortical and striatal neurons in vitro promotes the formation of functional CS synapses and is a widely used approach to elucidate pathogenic mechanisms of HD and to validate potential synapto-protective therapies...
June 27, 2018: BMC Biology
Rebecca Kusko, Jennifer Dreymann, Jermaine Ross, Yoonjeong Cha, Renan Escalante-Chong, Marta Garcia-Miralles, Liang Juin Tan, Michael E Burczynski, Ben Zeskind, Daphna Laifenfeld, Mahmoud Pouladi, Michal Geva, Iris Grossman, Michael R Hayden
BACKGROUND: Huntington Disease (HD) is an incurable autosomal dominant neurodegenerative disorder driven by an expansion repeat giving rise to the mutant huntingtin protein (mHtt), which is known to disrupt a multitude of transcriptional pathways. Pridopidine, a small molecule in development for treatment of HD, has been shown to improve motor symptoms in HD patients. In HD animal models, pridopidine exerts neuroprotective effects and improves behavioral and motor functions. Pridopidine binds primarily to the sigma-1 receptor, (IC50 ~ 100 nM), which mediates its neuroprotective properties, such as rescue of spine density and aberrant calcium signaling in HD neuronal cultures...
May 21, 2018: Molecular Neurodegeneration
Abraham Rosas-Arellano, Argel Estrada-Mondragón, Carola A Mantellero, Carlos Tejeda-Guzmán, Maite A Castro
γ-Aminobutyric acid (GABA), plays a key role in all stages of life, also is considered the main inhibitory neurotransmitter. GABA activates two kind of membrane receptors known as GABAA and GABAB , the first one is responsible to render tonic inhibition by pentameric receptors containing α4-6, β3, δ, or ρ1-3 subunits, they are located at perisynaptic and/or in extrasynaptic regions. The biophysical properties of GABAA tonic inhibition have been related with cellular protection against excitotoxic injury and cell death in presence of excessive excitation...
April 2018: Neural Regeneration Research
Joshua Barry, Garnik Akopian, Carlos Cepeda, Michael S Levine
The present study examined synaptic communication between direct and indirect output pathway striatal medium-sized spiny neurons (MSNs) and their target structures, the substantia nigra pars reticulata (SNr) and the external globus pallidus (GPe) in two mouse models of Huntington's disease (HD). Cre recombination, optogenetics, and whole-cell patch-clamp recordings were used to determine alterations in intrinsic and synaptic properties of SNr and GPe neurons from both male and female symptomatic R6/2 (>60 d) and presymptomatic (2 months) or symptomatic (10-12 months) YAC128 mice...
May 16, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Lorena I Petrella, João M Castelhano, Mario Ribeiro, José V Sereno, Sónia I Gonçalves, Mário N Laço, Michael R Hayden, A Cristina Rego, Miguel Castelo-Branco
Huntington's disease (HD) is a neurodegenerative disorder causing cognitive and motor impairments, evolving to death within 15-20 years after symptom onset. We previously established a mouse model with the entire human HD gene containing 128 CAG repeats (YAC128) which accurately recapitulates the natural history of the human disease. Defined time points in this natural history enable the understanding of longitudinal trajectories from the neurochemical and structural points of view using non-invasive high-resolution multi-modal imaging...
June 15, 2018: Human Molecular Genetics
Sonal Agrawal, Julia Fox, Baskaran Thyagarajan, Jonathan H Fox
Mitochondrial bioenergetic dysfunction is involved in neurodegeneration in Huntington's disease (HD). Iron is critical for normal mitochondrial bioenergetics but can also contribute to pathogenic oxidation. The accumulation of iron in the brain occurs in mouse models and in human HD. Yet the role of mitochondria-related iron dysregulation as a contributor to bioenergetic pathophysiology in HD is unclear. We demonstrate here that human HD and mouse model HD (12-week R6/2 and 12-month YAC128) brains accumulated mitochondrial iron and showed increased expression of iron uptake protein mitoferrin 2 and decreased iron-sulfur cluster synthesis protein frataxin...
May 20, 2018: Free Radical Biology & Medicine
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
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
Zahra Dargaei, Jee Yoon Bang, Vivek Mahadevan, C Sahara Khademullah, Simon Bedard, Gustavo Morrone Parfitt, Jun Chul Kim, Melanie A Woodin
Huntington's disease (HD) is classically characterized as a movement disorder, however cognitive impairments precede the motor symptoms by ∼15 y. Based on proteomic and bioinformatic data linking the Huntingtin protein (Htt) and KCC2, which is required for hyperpolarizing GABAergic inhibition, and the important role of inhibition in learning and memory, we hypothesized that aberrant KCC2 function contributes to the hippocampal-associated learning and memory deficits in HD. We discovered that Htt and KCC2 interact in the hippocampi of wild-type and R6/2-HD mice, with a decrease in KCC2 expression in the hippocampus of R6/2 and YAC128 mice...
February 13, 2018: Proceedings of the National Academy of Sciences of the United States of America
Marta Garcia-Miralles, Michal Geva, Jing Ying Tan, Nur Amirah Binte Mohammad Yusof, Yoonjeong Cha, Rebecca Kusko, Liang Juin Tan, Xiaohong Xu, Iris Grossman, Aric Orbach, Michael R Hayden, Mahmoud A Pouladi
Pridopidine is currently under clinical development for Huntington disease (HD), with on-going studies to better characterize its therapeutic benefit and mode of action. Pridopidine was administered either prior to the appearance of disease phenotypes or in advanced stages of disease in the YAC128 mouse model of HD. In the early treatment cohort, animals received 0, 10, or 30 mg/kg pridopidine for a period of 10.5 months. In the late treatment cohort, animals were treated for 8 weeks with 0 mg/kg or an escalating dose of pridopidine (10 to 30 mg/kg over 3 weeks)...
December 7, 2017: JCI Insight
Abeer Al-Gharaibeh, Rebecca Culver, Andrew N Stewart, Bhairavi Srinageshwar, Kristin Spelde, Laura Frollo, Nivya Kolli, Darren Story, Leela Paladugu, Sarah Anwar, Andrew Crane, Robert Wyse, Panchanan Maiti, Gary L Dunbar, Julien Rossignol
Huntington's disease (HD) is a genetic neurodegenerative disorder characterized by neuronal loss and motor dysfunction. Although there is no effective treatment, stem cell transplantation offers a promising therapeutic strategy, but the safety and efficacy of this approach needs to be optimized. The purpose of this study was to test the potential of intra-striatal transplantation of induced pluripotent stem cell-derived neural stem cells (iPS-NSCs) for treating HD. For this purpose, we developed mouse adenovirus-generated iPSCs, differentiated them into neural stem cells in vitro , labeled them with Hoechst, and transplanted them bilaterally into striata of 10-month old wild type (WT) and HD YAC128 mice...
2017: Frontiers in Neuroscience
Marja D Sepers, Amy Smith-Dijak, Jeff LeDue, Karolina Kolodziejczyk, Ken Mackie, Lynn A Raymond
Huntington's disease (HD) is an inherited neurodegenerative disease affecting predominantly striatum and cortex that results in motor and cognitive disorders. Before a motor phenotype, animal models of HD show aberrant cortical-striatal glutamate signaling. Here, we tested synaptic plasticity of cortical excitatory synapses onto striatal spiny projection neurons (SPNs) early in the YAC128 mouse model of HD. High-frequency stimulation-induced long-term depression, mediated by the endocannabinoid anandamide and cannabinoid receptor 1 (CB1), was significantly attenuated in male and female YAC128 SPNs...
January 17, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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 (mHTT)-induced oxidative stress in vitro through promotion of the Nrf2 antioxidant response...
January 15, 2018: Human Molecular Genetics
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
Ana C Silva, Ildete L Ferreira, Michael R Hayden, Elisabete Ferreiro, A Cristina Rego
Huntington's disease (HD) is caused by an expansion of CAG repeats in the HTT gene, leading to expression of mutant huntingtin (mHTT) and selective striatal neuronal loss, frequently associated with mitochondrial dysfunction and decreased support of brain-derived neurotrophic factor (BDNF). New neurons derived from the subventricular zone (SVZ) are apparently not able to rescue HD pathological features. Thus, we analyzed proliferation, migration and differentiation of adult SVZ-derived neural stem/progenitor cells (NSPC) from mild (6month-old (mo)) and late (10mo) symptomatic HD YAC128 mice expressing full-length (FL)-mHTT versus age-matched wild-type (WT) mice...
January 2018: Biochimica et biophysica acta. Molecular basis of disease
Andreas Neueder, Christian Landles, Rhia Ghosh, David Howland, Richard H Myers, Richard L M Faull, Sarah J Tabrizi, Gillian P Bates
We have previously shown that exon 1 of the huntingtin gene does not always splice to exon 2 resulting in the production of a small polyadenylated mRNA (HTTexon1) that encodes the highly pathogenic exon 1 HTT protein. The level of this read-through product is proportional to CAG repeat length and is present in all knock-in mouse models of Huntington's disease (HD) with CAG lengths of 50 and above and in the YAC128 and BACHD mouse models, both of which express a copy of the human HTT gene. We have now developed specific protocols for the quantitative analysis of the transcript levels of HTTexon1 in human tissue and applied these to a series of fibroblast lines and post-mortem brain samples from individuals with either adult-onset or juvenile-onset HD...
May 2, 2017: Scientific Reports
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