scholarly journals Establishment and maintenance of an R6/1 transgenic mouse colony and validation of its progressive neurological phenotype to study Huntington’s disease

2018 ◽  
Vol 5 (1) ◽  
Author(s):  
Lucía Gabriela García-Lara ◽  
Adriana Morales-Martínez ◽  
Quetzalli Denisse Angeles-López ◽  
Hilda Pedraza-Espitia ◽  
Iván Pérez-Neri ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Transgenic Mouse ◽  
Neurodegenerative Disorder ◽  
Transgenic Animal ◽  
Phenotypic Characteristics ◽  
Neurological Phenotype ◽  
Transgenic Animal Models ◽  
The Central Nervous System

Huntington’s disease (HD) is a hereditary neurodegenerative disorder of the central nervous system that mainly affects the basal ganglia and has no cure. The mutation is located at an abnormal expansion of the CAG triplet in the Huntingtin gene. Humans show psychiatric, behavioural and motor disorders. Transgenic animal models are essential to the study of HD since the disease only affects humans. Therefore, the aim of this article was to describe the formation and maintenance of and to validate the progressive neurological phenotype of an R6/1 transgenic mouse colony. To achieve our objective, the colony founder was imported from Jackson Laboratories, and the mice were kept under controlled environmental conditions. The animals were bred at the vivarium of the Instituto Nacional de Neurología y Neurocirugía Man­uel Velasco Suárez. The R6/1 transgenic mice were successfully bred and showed genetic and phenotypic characteristics similar to the ones previously reported. Our colony is currently established and validated with the condi­tions of our vivarium and has produced more than four generations of R6/1 mice. The establishment of the R6/1 colony and its maintenance through generation is an advantage since it allows us to follow the authenticity of the transgenic mice regarding their phenotypic and motor behaviours. Fur­thermore, these animals can be compared with other transgenic mice that reproduce some of the main characteristics of the disease manifested in hu­mans, making these transgenic R6/1 mice a useful tool for the study of HD.

scholarly journals Striatal Potassium Channel Dysfunction in Huntington's Disease Transgenic Mice

2005 ◽  
Vol 93 (5) ◽  
pp. 2565-2574 ◽  
Author(s):  
Marjorie A. Ariano ◽  
Carlos Cepeda ◽  
Christopher R. Calvert ◽  
Jorge Flores-Hernández ◽  
Elizabeth Hernández-Echeagaray ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mouse Models ◽  
Neurodegenerative Disorder ◽  
Projection Neurons ◽  
Electrophysiological Properties ◽  
Spiny Neurons ◽  
Subunit Expression ◽  
Dissociated Cells

Huntington's disease (HD) is a neurodegenerative disorder that mainly affects the projection neurons of the striatum and cerebral cortex. Genetic mouse models of HD have shown that neurons susceptible to the mutation exhibit morphological and electrophysiological dysfunctions before and during development of the behavioral phenotype. We used HD transgenic mouse models to examine inwardly and outwardly rectifying K+ conductances, as well as expression of some related K+ channel subunits. Experiments were conducted in slices and dissociated cells from two mouse models, the R6/2 and TgCAG100, at the beginning and after full development of overt behavioral phenotypes. Striatal medium-sized spiny neurons (MSNs) from symptomatic transgenic mice had increased input resistances, depolarized resting membrane potentials, and reductions in both inwardly and outwardly rectifying K+ currents. These changes were more dramatic in the R6/2 model than in the TgCAG100. Parallel immunofluorescence studies detected decreases in the expression of K+ channel subunit proteins, Kir2.1, Kir2.3, and Kv2.1 in MSNs, which contribute to the formation of the channel ionophores for these currents. Attenuation in K+ conductances and channel subunit expression contribute to altered electrophysiological properties of MSNs and may partially account for selective cellular vulnerability in the striatum.

scholarly journals What, When and How to Measure—Peripheral Biomarkers in Therapy of Huntington’s Disease

2021 ◽  
Vol 22 (4) ◽  
pp. 1561
Author(s):  
Lukasz Przybyl ◽  
Magdalena Wozna-Wysocka ◽  
Emilia Kozlowska ◽  
Agnieszka Fiszer
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Motor Deficits ◽  
Or Efficiency ◽  
Peripheral Tissues ◽  
Disease Symptoms ◽  
The Central Nervous System ◽  
Inflammatory Proteins ◽  
Scientific Attention

Among the main challenges in further advancing therapeutic strategies for Huntington’s disease (HD) is the development of biomarkers which must be applied to assess the efficiency of the treatment. HD is a dreadful neurodegenerative disorder which has its source of pathogenesis in the central nervous system (CNS) but is reflected by symptoms in the periphery. Visible symptoms include motor deficits and slight changes in peripheral tissues, which can be used as hallmarks for prognosis of the course of HD, e.g., the onset of the disease symptoms. Knowing how the pathology develops in the context of whole organisms is crucial for the development of therapy which would be the most beneficial for patients, as well as for proposing appropriate biomarkers to monitor disease progression and/or efficiency of treatment. We focus here on molecular peripheral biomarkers which could be used as a measurable outcome of potential therapy. We present and discuss a list of wet biomarkers which have been proposed in recent years to measure pre- and postsymptomatic HD. Interestingly, investigation of peripheral biomarkers in HD can unravel new aspects of the disease pathogenesis. This especially refers to inflammatory proteins or specific immune cells which attract scientific attention in neurodegenerative disorders.

scholarly journals Cdk5 phosphorylation of huntingtin reduces its cleavage by caspases

2005 ◽  
Vol 169 (4) ◽  
pp. 647-656 ◽  
Author(s):  
Shouqing Luo ◽  
Coralie Vacher ◽  
Janet E. Davies ◽  
David C. Rubinsztein
Keyword(s):  
Amino Acids ◽  
Transgenic Mice ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Cellular Membrane ◽  
Aggregate Formation ◽  
Polyq Tract ◽  
Polyq Expansion ◽  
In Cells

Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded polyglutamine (polyQ) tract in the huntingtin (htt) protein. Mutant htt toxicity is exposed after htt cleavage by caspases and other proteases release NH2-terminal fragments containing the polyQ expansion. Here, we show htt interacts and colocalizes with cdk5 in cellular membrane fractions. Cdk5 phosphorylates htt at Ser434, and this phosphorylation reduces caspase-mediated htt cleavage at residue 513. Reduced mutant htt cleavage resulting from cdk5 phosphorylation attenuated aggregate formation and toxicity in cells expressing the NH2-terminal 588 amino acids (htt588) of mutant htt. Cdk5 activity is reduced in the brains of HD transgenic mice compared with controls. This result can be accounted for by the polyQ-expanded htt fragments reducing the interaction between cdk5 and its activator p35. These data predict that the ability of cdk5 phosphorylation to protect against htt cleavage, aggregation, and toxicity is compromised in cells expressing toxic fragments of htt.

scholarly journals Neuroimmunology of Huntington’s Disease: Revisiting Evidence from Human Studies

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Natalia P. Rocha ◽  
Fabiola M. Ribeiro ◽  
Erin Furr-Stimming ◽  
Antonio L. Teixeira
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Genetic Disorder ◽  
Cag Repeat ◽  
Motor Dysfunction ◽  
Gene Encoding ◽  
Ultimate Cause ◽  
The Central Nervous System ◽  
Inflammatory Changes

Huntington’s disease (HD) is a neurodegenerative disorder characterized by selective loss of neurons in the striatum and cortex, which leads to progressive motor dysfunction, cognitive decline, and psychiatric disorders. Although the cause of HD is well described—HD is a genetic disorder caused by a trinucleotide (CAG) repeat expansion in the gene encoding for huntingtin (HTT) on chromosome 4p16.3—the ultimate cause of neuronal death is still uncertain. Apart from impairment in systems for handling abnormal proteins, other metabolic pathways and mechanisms might contribute to neurodegeneration and progression of HD. Among these, inflammation seems to play a role in HD pathogenesis. The current review summarizes the available evidence about immune and/or inflammatory changes in HD. HD is associated with increased inflammatory mediators in both the central nervous system and periphery. Accordingly, there have been some attempts to slow HD progression targeting the immune system.

The absence of the aryl hydrocarbon receptor in the R6/1 transgenic mouse model of Huntington’s disease improves the neurological phenotype

2021 ◽  
Vol 408 ◽  
pp. 113230
Author(s):  
Quetzalli D. Angeles-López ◽  
Lucia García-Lara ◽  
Nicolás Aguirre-Pineda ◽  
Rolando Castañeda-Arellano ◽  
Guillermo Elizondo-Azuela ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Aryl Hydrocarbon Receptor ◽  
Huntington’S Disease ◽  
Transgenic Mouse ◽  
Transgenic Mouse Model ◽  
Aryl Hydrocarbon ◽  
Neurological Phenotype

scholarly journals The sleep and circadian problems of Huntington’s disease: when, why and their importance

2020 ◽  
Author(s):  
Z. Voysey ◽  
S. V. Fazal ◽  
A. S. Lazar ◽  
R. A. Barker
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Transgenic Animal ◽  
Disease Stage ◽  
Disease Manifestation ◽  
Slow Progression ◽  
Transgenic Animal Models ◽  
Sleep Abnormalities ◽  
Early Disease Stage ◽  
Rare Opportunity

Abstract Introduction Mounting evidence supports the existence of an important feedforward cycle between sleep and neurodegeneration, wherein neurodegenerative diseases cause sleep and circadian abnormalities, which in turn exacerbate and accelerate neurodegeneration. If so, sleep therapies bear important potential to slow progression in these diseases. Findings This cycle is challenging to study, as its bidirectional nature renders cause difficult to disentangle from effect. Likewise, well-controlled intervention studies are often impractical in the setting of established neurodegenerative disease. It is this that makes understanding sleep and circadian abnormalities in Huntington’s disease (HD) important: as a monogenic fully penetrant neurodegenerative condition presenting in midlife, it provides a rare opportunity to study sleep and circadian abnormalities longitudinally, prior to and throughout disease manifestation, and in the absence of confounds rendered by age and comorbidities. It also provides potential to trial sleep therapies at a preclinical or early disease stage. Moreover, its monogenic nature facilitates the development of transgenic animal models through which to run parallel pre-clinical studies. HD, therefore, provides a key model condition through which to gain new insights into the sleep-neurodegeneration interface. Conclusions Here, we begin by summarising contemporary knowledge of sleep abnormalities in HD, and consider how well these parallel those of Alzheimer’s and Parkinson’s as more common neurodegenerative conditions. We then discuss what is currently known of the sleep-neurodegeneration cyclical relationship in HD. We conclude by outlining key directions of current and future investigation by which to advance the sleep-neurodegeneration field via studies in HD.

scholarly journals Altered neurotransmitter receptor expression in transgenic mouse models of Huntington's disease

1999 ◽  
Vol 354 (1386) ◽  
pp. 981-989 ◽  
Author(s):  
Jang-Ho J. Cha ◽  
Ariel S. Frey ◽  
Stephen A. Alsdorf ◽  
Julie A. Kerner ◽  
Christoph M. Kosinski ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Clinical Symptoms ◽  
Receptor Expression ◽  
Neurotransmitter Receptors ◽  
Neurotransmitter Receptor ◽  
Pathological Mechanism ◽  
Neurological Phenotype ◽  
The Brain

Alterations in neurotransmitter receptors are a pathological hallmark of the neurodegeneration seen in Huntington's disease (HD). However, the significance of these alterations has been uncertain, possibly reflecting simply the loss of brain cells. It is not known for certain whether the alteration of neurotransmitter receptors occurs before the onset of symptoms in human HD. Recently we developed transgenic mice that contain a portion of a human HD gene and develop a progressive abnormal neurological phenotype. Neurotransmitter receptors that are altered in HD (receptors for glutamate, dopamine, acetylcholine and adenosine) are decreased in the brain of transgenic mice, in some cases before the onset of behavioural or motor symptoms. In transgenic mice, neurotransmitter receptor alterations occur before neuronal death. Further, receptor alterations are selective in that certain receptors, namely N -methyl-D-aspartate and γ-aminobutyric acid receptors, are unaltered. Finally, receptor decreases are preceded by selective decreases in the corresponding mRNA species, suggesting the altered transcription of specific genes. These results suggest that (i) receptor decreases precede, and therefore might contribute to, the development of clinical symptoms, and (ii) altered transcription of specific genes might be a key pathological mechanism in HD.

scholarly journals Emerging Roles of Exosomes in Huntington’s Disease

2021 ◽  
Vol 22 (8) ◽  
pp. 4085
Author(s):  
Hanadi Ananbeh ◽  
Petr Vodicka ◽  
Helena Kupcova Skalnikova
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Cell Types ◽  
Neuroprotective Effects ◽  
The Central Nervous System

Huntington’s disease (HD) is a rare hereditary autosomal dominant neurodegenerative disorder, which is caused by expression of mutant huntingtin protein (mHTT) with an abnormal number of glutamine repeats in its N terminus, and characterized by intracellular mHTT aggregates (inclusions) in the brain. Exosomes are small extracellular vesicles that are secreted generally by all cell types and can be isolated from almost all body fluids such as blood, urine, saliva, and cerebrospinal fluid. Exosomes may participate in the spreading of toxic misfolded proteins across the central nervous system in neurodegenerative diseases. In HD, such propagation of mHTT was observed both in vitro and in vivo. On the other hand, exosomes might carry molecules with neuroprotective effects. In addition, due to their capability to cross blood-brain barrier, exosomes hold great potential as sources of biomarkers available from periphery or carriers of therapeutics into the central nervous system. In this review, we discuss the emerging roles of exosomes in HD pathogenesis, diagnosis, and therapy.

scholarly journals Hippocampal Neurogenesis, Cognitive Deficits and Affective Disorder in Huntington's Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Mark I. Ransome ◽  
Thibault Renoir ◽  
Anthony J. Hannan
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mouse Models ◽  
Adult Neurogenesis ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Brain Regions ◽  
Transgenic Animal ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis

Huntington’s disease (HD) is a neurodegenerative disorder caused by a tandem repeat expansion encoding a polyglutamine tract in the huntingtin protein. HD involves progressive psychiatric, cognitive, and motor symptoms, the selective pathogenesis of which remains to be mechanistically elucidated. There are a range of different brain regions, including the cerebral cortex and striatum, known to be affected in HD, with evidence for hippocampal dysfunction accumulating in recent years. In this review we will focus on hippocampal abnormalities, in particular, deficits of adult neurogenesis. We will discuss potential molecular mechanisms mediating disrupted hippocampal neurogenesis, and how this deficit of cellular plasticity may in turn contribute to specific cognitive and affective symptoms that are prominent in HD. The generation of transgenic animal models of HD has greatly facilitated our understanding of disease mechanisms at molecular, cellular, and systems levels. Transgenic HD mice have been found to show progressive behavioral changes, including affective, cognitive, and motor abnormalities. The discovery, in multiple transgenic lines of HD mice, that adult hippocampal neurogenesis and synaptic plasticity is disrupted, may help explain specific aspects of cognitive and affective dysfunction. Furthermore, these mouse models have provided insight into potential molecular mediators of adult neurogenesis deficits, such as disrupted serotonergic and neurotrophin signaling. Finally, a number of environmental and pharmacological interventions which are known to enhance adult hippocampal neurogenesis have been found to have beneficial affective and cognitive effects in mouse models, suggesting common molecular targets which may have therapeutic utility for HD and related diseases.

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