MJD84.2 transgenic mice (also called SCA3-YAC-84Q) harbor a YAC transgene that expresses a human ataxin 3 gene (ATXN3; also called Machado-Joseph disease [MJD], MJD1, or spinocerebellar ataxia 3 [SCA3]) modified with a human MJD/SCA3-associated 84 CAG repeat expansion [(CAG)2CAAAAGCAGCAA(CAG)78 repeat motif (Q3KQ80), also referred to as (CAG)84]. See below for comment on CAG repeat stability. These MJD84.2 transgenic mice may be useful in studying the progressive neurodegenerative processes underlying Machado-Joseph disease/spinocerebellar ataxia 3 (MJD/SCA3) pathogenesis and other polyglutamine and trinucleotide repeat disorders.
Hemizygous mice (MJD84.2) harbor two copies of the transgene at a single genomic integration site, with transgene expression levels and patterns almost identical to endogenous MJD. Transgene expression is widespread - detected in the cerebellum, cerebral cortex, heart, lung, spleen, liver and skeletal muscle. Stable transmission of the MJD1/CAG84 transgene has been demonstrated for multiple generations with a predicted frequency of about 50%.
Hemizygous mice are viable and fertile, exhibiting attenuated weight gain and a progressive neurological phenotype. The neurological phenotype is characterized by prominent gait abnormalities (~4 weeks), mild tremor, moderate hypoactivity, forelimb/hindlimb clasping (~24 weeks), inability to correct during negative geotaxis (~20 weeks), marked neuronal degeneration and mild gliosis of the dentate and pontine nerve nuclei, atrophy of the cerebellar Purkinje and molecular cell layers, and increased neuronal intranuclear inclusions (NIIs) that are ubiquitinated. With age, mice develop deficits in beam walking and gait walking assays, as well as neuronal loss in pontine nuclei and substantia nigra regions.
Homozygous mice (MJD84.2/84.2) exhibit increased severity and earlier onset of symptoms, as well as excessive grooming.
For these MJD84.2 mice, the donating investigator did not sequence the CAG repeat expansion over time. It is unknown if the CAG repeat number is subject to germline and somatic instability (whether it may expand or contract). When using lines with CAG repeat length, it is strongly recommended the CAG repeat number be quantified in all the experimental animals; all animals in all experimental groups should carry comparable CAG repeat sizes. CAG repeat sizing in mice should be done using high-resolution methods; as assays based on agarose gel electrophoresis may not provide sufficient resolution to accurately measure CAG repeat numbers. If labs do not have access to the appropriate equipment for determining CAG repeat length, CAG repeats can be evaluated on a fee-for-service basis by Laragen, Inc.
It is the experience of The Jackson Laboratory that the CAG repeat values of hemizygous MJD84.2 mice (a single genomic integration of two copies of the transgene) have been generally consistent over time, with the Laragen assay reporting ~65-78 CAG repeats [June 2020].
