A transgenic mouse model of spinocerebellar ataxia type 3 resembling late disease onset and gender-specific instability of CAG repeats

Boy, Jana; Schmidt, Thorsten; Schumann, Ulrike; Grasshoff, Ute; Unser, Samy; Holzmann, Carsten; Schmitt, Imke; Karl, Tim; Laccone, Franco; Wolburg, Hartwig; Ibrahim, Saleh M.; Rieß, Olaf

doi:10.1016/j.nbd.2009.08.002

Cited by 52 publications

(46 citation statements)

References 67 publications

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“…Moreover, neuronal inclusions were observed already at 20 but not at 16 weeks of age, when several motor symptoms were already clearly present. This is in agreement with previous results obtained in other transgenic mouse models of MJD, in which symptoms appear before the detection of the inclusions [40].…”

Section: Discussionsupporting

confidence: 93%

Chronic Treatment with 17-DMAG Improves Balance and Coordination in A New Mouse Model of Machado-Joseph Disease

et al. 2014

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Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease currently with no treatment. We describe a novel mouse model of MJD which expresses mutant human ataxin-3 at near endogenous levels and manifests MJD-like motor symptoms that appear gradually and progress over time. CMVMJD135 mice show ataxin-3 intranuclear inclusions in the CNS and neurodegenerative changes in key disease regions, such as the pontine and dentate nuclei. Hsp90 inhibition has shown promising outcomes in some neurodegenerative diseases, but nothing is known about its effects in MJD. Chronic treatment of CMVMJD mice with Hsp90 inhibitor 17-DMAG resulted in a delay in the progression of their motor coordination deficits and, at 22 and 24 weeks of age, was able to rescue the uncoordination phenotype to wild-type levels; in parallel, a reduction in neuropathology was observed in treated animals. We observed limited induction of heat-shock proteins with treatment, but found evidence that 17-DMAG may be acting through autophagy, as LC3-II (both at mRNA and protein levels) and beclin-1 were induced in the brain of treated animals. This resulted in decreased levels of the mutant ataxin-3 and reduced intranuclear aggregation of this protein.Our data validate this novel mouse model as a relevant tool for the study of MJD pathogenesis and for pre-clinical studies, and show that Hsp90 inhibition is a promising therapeutic strategy for MJD.

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Section: Discussionsupporting

confidence: 93%

Chronic Treatment with 17-DMAG Improves Balance and Coordination in A New Mouse Model of Machado-Joseph Disease

et al. 2014

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“…To attempt to answer these questions, several transgenic mouse models of MJD were created using different promoters to drive the expression of the human cDNA/gene: the L7 specific Purkinje cell promoter (Ikeda et al, 1996); the ATXN3 promoter (Cemal et al, 2002); the HD promoter (Boy et al, 2009a); and different portions of the PrP promoter (which originates high brain expression levels) (Bichelmeier et al, 2007;Chou et al, 2008;Goti et al, 2004). More recently, a conditional MJD mouse model using the Tet-Off system was described showing reversibility of the phenotype (Boy et al, 2009b).…”

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confidence: 99%

Motor uncoordination and neuropathology in a transgenic mouse model of Machado–Joseph disease lacking intranuclear inclusions and ataxin-3 cleavage products

Silva‐Fernandes

Costa

Duarte‐Silva

et al. 2010

Neurobiology of Disease

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Machado-Joseph disease (MJD) is a late-onset neurodegenerative disorder caused by a polyglutamine (polyQ) expansion in the ataxin-3 protein. We generated two transgenic mouse lineages expressing the expanded human ataxin-3 under the control of the CMV promoter: CMVMJD83 and CMVMJD94, carrying Q83 and Q94 stretches, respectively. Behavioral analysis revealed that the CMVMJD94 transgenic mice developed motor uncoordination, intergenerational instability of the CAG repeat and a tissue-specific increase in the somatic mosaicism of the repeat with aging. Histopathological analysis of MJD mice at early and late stages of the disease revealed neuronal atrophy and astrogliosis in several brain regions; however, we found no signs of microglial activation or neuroinflammatory response prior to the appearance of an overt phenotype. In our model, the appearance of MJD-like symptoms was also not associated with the presence of ataxin-3 cleavage products or intranuclear aggregates. We propose the transgenic CMVMJD94 mice as a useful model to study the early stages in the pathogenesis of MJD and to explore the molecular mechanisms involved in CAG repeat instability.

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“…For each of the next 7 transgenic mice generated [32][33][34][35][36][37][38]: the transgenic mouse construct, behavior/signs, and pathology are summarized as follows.…”

Section: Mouse Modelsmentioning

confidence: 99%

“…For mouse model 6 [37], the transgenic construct contains the cDNA encoding isoform ataxin-3c with 148 CAG, a partial rat huntingtin promoter (764 bp: -777 to -14), and a SV40 mRNA polyadenylation signal. Expression is widespread expression.…”

Section: Mouse Modelmentioning

confidence: 99%

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Mouse Models of Spinocerebellar Ataxia Type 3 (Machado-Joseph Disease)

Gould

2012

Neurotherapeutics

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A transgenic mouse model of spinocerebellar ataxia type 3 resembling late disease onset and gender-specific instability of CAG repeats

Cited by 52 publications

References 67 publications

Chronic Treatment with 17-DMAG Improves Balance and Coordination in A New Mouse Model of Machado-Joseph Disease

Chronic Treatment with 17-DMAG Improves Balance and Coordination in A New Mouse Model of Machado-Joseph Disease

Motor uncoordination and neuropathology in a transgenic mouse model of Machado–Joseph disease lacking intranuclear inclusions and ataxin-3 cleavage products

Mouse Models of Spinocerebellar Ataxia Type 3 (Machado-Joseph Disease)

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