Animal models of Huntington's disease: implications in uncovering pathogenic mechanisms and developing therapies

Wang, Linhui; Qin, Zheng‐Hong

doi:10.1111/j.1745-7254.2006.00410.x

Cited by 28 publications

(9 citation statements)

References 113 publications

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“…There are many particular types of mouse models for Huntington’s disease, including mice that contain only a fragment of exon-1 of the human huntingtin gene containing polyglutamine mutations (this in addition to both alleles of murine wild-type huntingtin, Hdh), mice with pathogenic CAG repeats inserted into existing CAG expansion in the murine huntingtin Hdh (knock ins), and mice that express the full-length human HD gene (including murine Hdh) (Adhihetty and Beal 2008; Wang and Qin 2006). One such strain, called R6/2, generated with approximately 155 CAG repeats inserted into their huntingtin genes, show subtle motor deficiencies and learning deficits one month after birth, with symptoms becoming more pronounced at two months, and becoming fatal at three to four months (Levine et al 2004).…”

Section: In Vivo Modeling Of Mitochondrial Dysfunctionmentioning

confidence: 99%

Modeling mitochondrial dysfunctions in the brain: from mice to men

Breuer

Willems

Rüssel

et al. 2011

J of Inher Metab Disea

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The biologist Lewis Thomas once wrote: “my mitochondria comprise a very large proportion of me. I cannot do the calculation, but I suppose there is almost as much of them in sheer dry bulk as there is the rest of me”. As humans, or indeed as any mammal, bird, or insect, we contain a specific molecular makeup that is driven by vast numbers of these miniscule powerhouses residing in most of our cells (mature red blood cells notwithstanding), quietly replicating, living independent lives and containing their own DNA. Everything we do, from running a marathon to breathing, is driven by these small batteries, and yet there is evidence that these molecular energy sources were originally bacteria, possibly parasitic, incorporated into our cells through symbiosis. Dysfunctions in these organelles can lead to debilitating, and sometimes fatal, diseases of almost all the bodies’ major organs. Mitochondrial dysfunction has been implicated in a wide variety of human disorders either as a primary cause or as a secondary consequence. To better understand the role of mitochondrial dysfunction in human disease, a multitude of pharmacologically induced and genetically manipulated animal models have been developed showing to a greater or lesser extent the clinical symptoms observed in patients with known and unknown causes of the disease. This review will focus on diseases of the brain and spinal cord in which mitochondrial dysfunction has been proven or is suspected and on animal models that are currently used to study the etiology, pathogenesis and treatment of these diseases.

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Section: In Vivo Modeling Of Mitochondrial Dysfunctionmentioning

confidence: 99%

Modeling mitochondrial dysfunctions in the brain: from mice to men

Breuer

Willems

Rüssel

et al. 2011

J of Inher Metab Disea

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“…Occurring shortly thereafter was the development of other genetically altered mouse lines, including transgenic, knock-in, knock-out, and virally-inserted variants, that model human HD in different ways and to various extents (reviewed in Menalled and Chesselet, 2002; Levine et al, 2004; Menalled, 2005; Wang and Qin, 2006). For example, yeast artificial chromosome-128 (YAC128) mice, which express the full length IT15 gene with 128 CAG repeats, showed a less aggressive disease progression compared to R6/2 mice: hyperkinesis at 3 months, hypokinesis at 6 months, and significant motor impairment at 12 months (Slow et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Motor function and dopamine release measurements in transgenic Huntington's disease model rats

Ortiz¹,

Osterhaus²,

Lauderdale³

et al. 2012

Brain Research

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Huntington’s disease (HD) is a fatal, genetic, neurodegenerative disorder characterized by deficits in motor and cognitive function. Here, we have quantitatively characterized motor deficiencies and dopamine release dynamics in transgenic HD model rats. Behavioral analyses were conducted using a newly-developed force-sensing runway and a previously-developed force-plate actometer. Gait disturbances were readily observed in transgenic HD rats at 12 to 15 months of age. Additionally, dopamine system challenge by ip injection of amphetamine also revealed that these rats were resistant to the expression of focused stereotypy compared to wild-type controls. Moreover, dopamine release, evoked by the application of single and multiple electrical stimulus pulses applied at different frequencies, and measured using fast-scan cyclic voltammetry at carbon-fiber microelectrodes, was diminished in transgenic HD rats compared to age-matched wild-type control rats. Collectively, these results underscore the potential contribution of dopamine release alterations to the expression of motor impairments in transgenic HD rats.

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“…Many HD models including chemically induced models and genetic models can mimic some aspects of HD symptoms and pathology [7]. In vivo studies conducted with animal models have revealed much pathogenesis of this disease.…”

Section: Introductionmentioning

confidence: 99%

High efficiency adenovirus-mediated expression of truncated N-terminal huntingtin fragment (htt552) in primary rat astrocytes

Wang¹,

Lin²,

Wu³

et al. 2009

ABBS

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Huntington's disease (HD) is caused by an expansion of polyglutamine tract in N-terminus of huntingtin (htt). The mutation of htt leads to dysfunction and premature death of striatal and cortical neurons. However, the effects of htt mutation on glia remain largely unknown. This study aimed to establish a glia HD model using an adenoviral vector to express wild-type and mutant N-terminal huntingtin fragment 1-552 amino acids (htt552) in rat primary cortical astrocytes. We have evaluated optimal conditions for the infection of astrocytes with adenoviral vectors, and the kinetics of the expression of htt552 in astrocytes. The majority of astrocytes expressed the transgene after infection. At 24 h postinfection, the highest rate of infection was 89 + + + + + 3% for the wild-type (htt552-18Q) with a multiplicity of infection (m.o.i.) of 80, and the highest rate of infection was 91 + + + + + 4% for the mutant type (htt552-100Q) with the same viral dose. The duration of expression of htt552 lasted for about 7 days with a relatively high level from 1 to 4 days post-infection. Mutant huntingtin (htt552-100Q) produced the characteristic HD pathology after 3 days by the appearance of cytoplasmic aggregates and intranuclear inclusions. The result of MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) assay showed that the inhibition of viability by virus on astrocytes was also dose-dependent. To obtain high infection rate and low toxicity, the viral dose with an m.o.i. of 40 was optimal to our cell model. The present study demonstrates that adenoviral-mediated expression of mutant htt provides an advantageous system for histological and biochemical analysis of HD pathogenesis in primary cortical astrocyte cultures.

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Animal models of Huntington's disease: implications in uncovering pathogenic mechanisms and developing therapies

Cited by 28 publications

References 113 publications

Modeling mitochondrial dysfunctions in the brain: from mice to men

Modeling mitochondrial dysfunctions in the brain: from mice to men

Motor function and dopamine release measurements in transgenic Huntington's disease model rats

High efficiency adenovirus-mediated expression of truncated N-terminal huntingtin fragment (htt552) in primary rat astrocytes

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