Polyglutamine-expanded ataxin-3 causes cerebellar dysfunction of SCA3 transgenic mice by inducing transcriptional dysregulation

Chou, An Hsun; Yeh, Tu Hsueh; Ouyang, Pin; Chen, Ying Ling; Chen, Si Ying; Wang, Hung Li

doi:10.1016/j.nbd.2008.03.011

Cited by 167 publications

(161 citation statements)

References 67 publications

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“…We chose to study animals with repeat lengths over 129. All the comparisons for the genotype factor were performed between CMVMJD135 mice and wild-type littermates since it has been previously shown that transgenic mice expressing human ataxin-3 carrying a normal CAG repeat tract did not display any differences in the phenotype or neuropathology in comparison with wild-type (wt) [27][28][29][30]. In addition, our previous data have shown that even expression of ataxin-3 with 83 glutamines under the CMV promoter caused no phenotype change [31].…”

Section: Cmvmjd135 Mice Express the Expanded Human Ataxin-3 In The Cnsmentioning

confidence: 99%

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: Cmvmjd135 Mice Express the Expanded Human Ataxin-3 In The Cnsmentioning

confidence: 99%

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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“…2) Model 4 (and predictable model 1) has transcriptional dysregulation in the cerebellum [35], which is reversible with sodium butyrate [52].…”

Section: Discussionmentioning

confidence: 99%

“…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 4 [35], isoform MJD1a with 79 or 22 CAG with an N-terminal hemagglutinin tag are expressed using the same vector described for model 2. The transgenic mice were maintained on a FVB/N genetic background.…”

Section: Mouse Modelmentioning

confidence: 99%

“…Mouse model 4 [35], line ataxin-3-Q79HA: 1) Intranuclear inclusions in neurons: at 10 to 12 months, neuronal inclusions were detected in pons, dentate nuclei, and substantia nigra. It is not clear whether other brain regions were analyzed.…”

Section: Mouse Modelmentioning

confidence: 99%

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