Abstract
Huntington’s disease (HD) is caused by the expansion of a CAG repeat in the huntingtin (HTT) gene. The R6 mouse models of HD express a mutant version of exon 1 HTT and typically develop motor and cognitive impairments, a widespread huntingtin (HTT) aggregate pathology and brain atrophy. Unlike the more commonly used R6/2 mouse line, R6/1 mice have fewer CAG repeats and, subsequently, a less rapid pathological decline. Compared to the R6/2 line, fewer descriptions of the progressive pathologies exhibited by R6/1 mice exist. The association between the molecular and cellular neuropathology with brain atrophy, and with the development of behavioral phenotypes remains poorly understood in many models of HD. In attempt to link these factors in the R6/1 mouse line, we have performed detailed assessments of behavior and of regional brain abnormalities determined through longitudinal, in vivo magnetic resonance imaging (MRI), as well as an end-stage, ex vivo MRI study and histological assessment. We found progressive decline in both motor and non-motor related behavioral tasks in R6/1 mice, first evident at 11 weeks of age. Regional brain volumes were generally unaffected at 9 weeks, but by 17 weeks there was significant grey matter atrophy. This age-related brain volume loss was validated using a more precise, semi-automated Tensor Based morphometry assessment. As well as these clear progressive phenotypes, mutant HTT (mHTT) protein, the hallmark of HD molecular pathology, was widely distributed throughout the R6/1 brain and was accompanied by neuronal loss. Despite these seemingly concomitant, robust pathological phenotypes, there appeared to be little correlation between the three main outcome measures: behavioral performance, MRI-detected brain atrophy and histopathology. In conclusion, R6/1 mice exhibit many features of HD, but the underlying mechanisms driving these clear behavioral disturbances and the brain volume loss, still remain unclear.
Highlights
Huntington’s disease (HD), a progressive, autosomal dominant neurological disorder, is caused by a CAG/ polyglutamine repeat expansion [1]
We have previously described the concomitant behavioral dysfunction and development of brain abnormalities detected through magnetic resonance imaging (MRI) exhibited by the R6/2 mouse line, expressing ~210 CAG repeats [19]
Abnormal weight gain is a common feature of mouse models of HD
Summary
Huntington’s disease (HD), a progressive, autosomal dominant neurological disorder, is caused by a CAG/ polyglutamine repeat expansion [1]. The varying nature of HD, as well as the scarcity of affected tissue during the early stages of disease, impede efforts to link molecular pathology to both brain atrophy and motor/behavioral dysfunction. To overcome such issues and improve our understanding of the causes of HD, a variety of rodent models have been developed. We have subsequently shown that this is generated through the mis-splicing of exon 1, indicating that the R6 mice are a model for the aberrant splicing that occurs in HD [18] This current study is part of a continuing detailed comparison of the progressive pathologies exhibited by the R6 and knock-in mouse models
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
