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

Abstract

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.

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

“…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].…”

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

“…This fragment was not detected in non-neuronal tissue in model 2 [42]. Such a fragment was not detected in the brain of mouse models with intermediate (model 1, [32]) or low severity phenotype (model 7, [38]). The fragment is probably present in the brain of intermediate and low severity mouse models, but at levels that are not readily detectable, as observed in the brain of Q71-B heterozygous transgenic mice [33].…”

“…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.…”

“…For mouse model 7 [38], the transgenic construct contains the cDNA encoding isoform ataxin-3c with 94 CAG, a CMV promoter (details were not reported), and a SV40 mRNA polyadenylation signal. Expression is widespread.…”

“…Mouse model 7 [38], hemi-CMVMJD94: 1) Intranuclear inclusions in neurons: at 12 months, no neuronal intranuclear inclusions were detected. 2) Neurodegeneration: a) decrease in number of neurons stained with a dye or antibody: not reported.…”