YAC transgenic mice carrying pathological alleles of the MJD1 locus exhibit a mild and slowly progressive cerebellar deficit

Abstract

Machado-Joseph disease (MJD; MIM 109150) is a late-onset neurodegenerative disorder caused by the expansion of a polyglutamine tract within the MJD1 gene. We have previously reported the generation of human yeast artificial chromosome (YAC) constructs encompassing the MJD1 locus into which expanded (CAG)(76) and (CAG)(84) repeat motifs have been introduced by homologous recombination. Transgenic mice containing pathological alleles with polyglutamine tract lengths of 64, 67, 72, 76 and 84 repeats, as well as the wild type with 15 repeats, have now been generated using these YAC constructs. The mice with expanded alleles demonstrate a mild and slowly progressive cerebellar deficit, manifesting as early as 4 weeks of age. As the disease progresses, pelvic elevation becomes markedly flattened, accompanied by hypotonia, and motor and sensory loss. Neuronal intranuclear inclusion (NII) formation and cell loss is prominent in the pontine and dentate nuclei, with variable cell loss in other regions of the cerebellum from 4 weeks of age. Interestingly, peripheral nerve demyelination and axonal loss is detected in symptomatic mice from 26 weeks of age. In contrast, transgenic mice carrying the wild-type (CAG)(15) allele of the MJD1 locus appear completely normal at 20 months. Disease severity increases with the level of expression of the expanded protein and the size of the repeat. These mice are representative of MJD and will be a valuable resource for the detailed analysis of the roles of repeat length, tissue specificity and level of expression in the neurodegenerative processes underlying MJD pathogenesis.

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

“…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 1 [32], the transgenic construct contains the MJD1 gene with 84 or 15 CAG and is flanked at the 5′end by 35 kb and at the 3′end by 150 kb of the SCA3 locus and the arms of the yeast artificial chromosome. All ataxin-3 isoforms (including MJD1a and ataxin-3c) could be synthesized; the human ataxin-3 promoter drives widespread expression (see Introduction for details).…”

“…Mouse model 1 [32], line 84.2 had: 1) lower body weight: 12 to 22 % at 1 to 5 months of age; 2) reduced balance/ coordination: inability to turn on a grid [32], and reduced beam-walking ability at 7.5 to 13 months in another report [40]; 3) abnormal gait: wide-based limbs at 1 month [32], and shorter stride-alternated footprint pattern at 13.5 months, as described in another report [40]; 4) locomotor hypoactivity: described as inactivity; 5) abnormal limb position when held by tail: forelimb clasping at 6 months, and all limb clasping at 14 months (instead of normal escape reflexes, which is limb spreading); and 6) premature death: not reported, but could not have occurred before 13.5 months because tests were done on animals at this age.…”

“…Mouse model 1 [32], line 84.2: 1) Intranuclear inclusions in neurons: detected in pontine and dentate nuclei. It is unclear if substantia nigra was analyzed.…”

C‐terminal deletion of the atrophin‐1 protein results in growth retardation but not neurodegeneration in mice

“…Disease genes share no sequence homology except for the poly-Q coding sequences, indicating a critical role of the glutamine expansion in pathogenesis (Igarashi et al, 1998). In addition to DRPLA, expression of poly-Q expanded mutant proteins identified in HD, SCA1, SCA3, or SCA7 also induced neurodegeneration in mice (Mangiarini et al, 1996;Clark et al, 1997;Davies et al, 1997;Yvert et al, 2000;Cemal et al, 2002;Benn et al, 2005). Dominant inheritance of these diseases is consistent with a neomorphic feature of the poly-Q expansion.…”